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Guo B, Shi S, Xiong J, Guo Y, Wang B, Bai L, Qiu Y, Li S, Gao D, Dong Z, Tu Y. Identification of potential biomarkers in cardiovascular calcification based on bioinformatics combined with single-cell RNA-seq and multiple machine learning analysis. Cell Signal 2025; 131:111705. [PMID: 40024421 DOI: 10.1016/j.cellsig.2025.111705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Revised: 02/25/2025] [Accepted: 02/26/2025] [Indexed: 03/04/2025]
Abstract
BACKGROUND The molecular and genetic mechanisms underlying vascular calcification remain unclear. This study aimed to determine the differences in calcification marker-related gene expression in macrophages. METHODS The expression profiling datasets GSE104140 and GSE235995 were analysed to identify differentially expressed genes (DEGs) between fibroatheroma with calcification and diffuse intimal thickening. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, Weighted Gene Co-expression Network Analysis (WGCNA), and Gene Set Enrichment Analysis (GSEA) were performed to assess functional characteristics. Hub genes were identified through a protein-protein interaction (PPI) network and machine learning approaches. Single-cell RNA sequencing data (GSE159677) validated the expression of calcification-related genes in macrophages, while Mendelian randomization analysis explored their potential causal relationship with coronary calcification. Further validation was conducted using enzyme-linked immunosorbent assay (ELISA) on coronary calcification samples and immunohistochemistry in ApoE-/- mice. Intravascular ultrasound was performed to assess coronary calcification severity. RESULTS AND CONCLUSIONS Two key biomarkers, ITGAX and MYD88, were identified as diagnostic indicators of cardiovascular calcification. Both biomarkers were significantly upregulated in calcified samples and were strongly associated with immune processes. Single-cell RNA sequencing confirmed their high expression in multiple immune cell types. Additionally, molecular docking analysis revealed that retinoic acid interacted with both biomarkers, suggesting potential therapeutic relevance. Immunohistochemical and ELISA analyses further validated their elevated expression in calcified samples. These findings provide novel insights into the molecular mechanisms of vascular calcification and highlight potential diagnostic and therapeutic targets.
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Affiliation(s)
- Bingchen Guo
- Harbin Medical University, Harbin, China; Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin 150000, China.
| | - Si Shi
- Harbin Medical University, Harbin, China; Department of Respirology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150000, China
| | - Jie Xiong
- Harbin Medical University, Harbin, China; Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin 150000, China
| | - Yutong Guo
- Harbin Medical University, Harbin, China; Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin 150000, China
| | - Bo Wang
- Harbin Medical University, Harbin, China; Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin 150000, China
| | - Liyan Bai
- Harbin Medical University, Harbin, China; Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin 150000, China
| | - Yi Qiu
- Harbin Medical University, Harbin, China; Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin 150000, China
| | - Shucheng Li
- Harbin Medical University, Harbin, China; Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin 150000, China
| | - Dianyu Gao
- Harbin Medical University, Harbin, China; Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin 150000, China
| | - Zengxiang Dong
- Harbin Medical University, Harbin, China; Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin 150000, China
| | - Yingfeng Tu
- Harbin Medical University, Harbin, China; Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin 150000, China; Department of Cardiology, The Shanxi Provincial People's Hospital, Taiyuan 030000, China.
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2
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Saadh MJ, Muhammad FA, Albadr RJ, Sanghvi G, Ballal S, Pathak PK, Bareja L, Aminov Z, Taher WM, Alwan M, Jawad MJ, Al-Nuaimi AMA. Exosomal non-coding RNAs: key regulators of inflammation-related cardiovascular disorders. Eur J Med Res 2025; 30:395. [PMID: 40390035 PMCID: PMC12087048 DOI: 10.1186/s40001-025-02649-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2025] [Accepted: 04/30/2025] [Indexed: 05/21/2025] Open
Abstract
Inflammation is a complex, tightly regulated process involving biochemical and cellular reactions to harmful stimuli. Often termed "the internal fire", it is crucial for protecting the body and facilitating tissue healing. While inflammation is essential for survival, chronic inflammation can be detrimental, leading to tissue damage and reduced survival. The innate immune system triggers inflammation, closely linked to the development of heart diseases, with significant consequences for individuals. Inflammation in arterial walls or the body substantially contributes to atherosclerotic disease progression, affecting the cardiovascular system. Altered lipoproteins increase the risk of excessive blood clotting, a hallmark of atherosclerotic cardiovascular disease and its complications. Integrating inflammatory biomarkers with established risk assessment techniques can enhance our ability to identify at-risk individuals, assess their risk severity, and recommend appropriate CVD prevention strategies. Exosomes, a type of extracellular vesicle, are released by various cells and mediate cell communication locally and systemically. In the past decade, exosomes have been increasingly studied for their vital roles in health maintenance and disease processes. They can transport substances like non-coding RNAs, lipids, and proteins between cells, influencing immune responses and inflammation to elicit harmful or healing effects. This study focuses on the critical role of inflammation in heart disease progression and how non-coding RNAs in exosomes modulate the inflammatory process, either exacerbating or alleviating inflammation-related damage in the cardiovascular system.
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Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman, 11831, Jordan
| | | | | | - Gaurav Sanghvi
- Marwadi University Research Center, Department of Microbiology, Faculty of Science, Marwadi University, Rajkot, Gujarat, 360003, India
| | - Suhas Ballal
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to Be University), Bangalore, Karnataka, India
| | - Piyus Kumar Pathak
- Department of Applied Sciences-Chemistry, NIMS Institute of Engineering & Technology, NIMS University Rajasthan, Jaipur, India
| | - Lakshay Bareja
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, Punjab, 140401, India
| | - Zafar Aminov
- Department of Public Health and Healthcare Management, Samarkand State Medical University, 18 Amir Temur Street, Samarkand, Uzbekistan
| | - Waam Mohammed Taher
- College of Nursing, National University of Science and Technology, Dhi Qar, Iraq
| | - Mariem Alwan
- Pharmacy College, Al-Farahidi University, Baghdad, Iraq
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3
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Zimbru RI, Zimbru EL, Bojin FM, Haidar L, Andor M, Harich OO, Tănasie G, Tatu C, Mailat DE, Zbîrcea IM, Hirtie B, Uța C, Bănărescu CF, Panaitescu C. Connecting the Dots: How MicroRNAs Link Asthma and Atherosclerosis. Int J Mol Sci 2025; 26:3570. [PMID: 40332077 PMCID: PMC12026532 DOI: 10.3390/ijms26083570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2025] [Revised: 04/07/2025] [Accepted: 04/08/2025] [Indexed: 05/08/2025] Open
Abstract
Asthma and atherosclerosis are chronic conditions with distinct pathophysiologies, but overlapping inflammatory mechanisms that suggest a potential common regulatory framework. MicroRNAs (miRNAs), small non-coding RNA molecules that modulate gene expression post-transcriptionally, could be key players in linking these disorders. This review outlines how miRNAs contribute to the complex interplay between asthma and atherosclerosis, focusing on key miRNAs involved in inflammatory pathways, immune cell regulation and vascular remodeling. We discuss specific miRNAs, such as miR-155, miR-21 and miR-146a, which have been shown to modulate inflammatory cytokine production and T cell differentiation, impacting respiratory and cardiovascular health. The common miRNAs found in both asthma and atherosclerosis emphasize their role as potential biomarkers, but also as therapeutic targets. Understanding these molecular connections may unlock novel approaches for innovative, integrated treatment strategies that address both conditions and may significantly improve patient outcomes. Further research is needed to explore mechanistic pathways and validate the translational potential of miRNA-based interventions in preclinical and clinical settings.
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Affiliation(s)
- Răzvan-Ionuț Zimbru
- Center of Immuno-Physiology and Biotechnologies, Department of Functional Sciences, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (R.-I.Z.)
- Research Center for Gene and Cellular Therapies in the Treatment of Cancer—OncoGen, Timis County Emergency Clinical Hospital “Pius Brinzeu”, 156 Liviu Rebreanu Bd., 300723 Timisoara, Romania
| | - Elena-Larisa Zimbru
- Center of Immuno-Physiology and Biotechnologies, Department of Functional Sciences, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (R.-I.Z.)
- Research Center for Gene and Cellular Therapies in the Treatment of Cancer—OncoGen, Timis County Emergency Clinical Hospital “Pius Brinzeu”, 156 Liviu Rebreanu Bd., 300723 Timisoara, Romania
- Multidisciplinary Heart Research Center, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Florina-Maria Bojin
- Center of Immuno-Physiology and Biotechnologies, Department of Functional Sciences, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (R.-I.Z.)
- Research Center for Gene and Cellular Therapies in the Treatment of Cancer—OncoGen, Timis County Emergency Clinical Hospital “Pius Brinzeu”, 156 Liviu Rebreanu Bd., 300723 Timisoara, Romania
- Timis County Emergency Clinical Hospital “Pius Brinzeu”, 156 Liviu Rebreanu Bd., 300723 Timisoara, Romania
| | - Laura Haidar
- Center of Immuno-Physiology and Biotechnologies, Department of Functional Sciences, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (R.-I.Z.)
| | - Minodora Andor
- Multidisciplinary Heart Research Center, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania
- Cardiology Clinic, Timisoara Municipal Clinical Emergency Hospital, 12 Revoluției din 1989 Bd., 300040 Timisoara, Romania
| | - Octavia Oana Harich
- Center of Immuno-Physiology and Biotechnologies, Department of Functional Sciences, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (R.-I.Z.)
| | - Gabriela Tănasie
- Center of Immuno-Physiology and Biotechnologies, Department of Functional Sciences, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (R.-I.Z.)
- Research Center for Gene and Cellular Therapies in the Treatment of Cancer—OncoGen, Timis County Emergency Clinical Hospital “Pius Brinzeu”, 156 Liviu Rebreanu Bd., 300723 Timisoara, Romania
- Timis County Emergency Clinical Hospital “Pius Brinzeu”, 156 Liviu Rebreanu Bd., 300723 Timisoara, Romania
| | - Carmen Tatu
- Center of Immuno-Physiology and Biotechnologies, Department of Functional Sciences, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (R.-I.Z.)
- Research Center for Gene and Cellular Therapies in the Treatment of Cancer—OncoGen, Timis County Emergency Clinical Hospital “Pius Brinzeu”, 156 Liviu Rebreanu Bd., 300723 Timisoara, Romania
- Timis County Emergency Clinical Hospital “Pius Brinzeu”, 156 Liviu Rebreanu Bd., 300723 Timisoara, Romania
| | - Diana-Evelyne Mailat
- Multidisciplinary Heart Research Center, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania
- Cardiology Clinic, Timisoara Municipal Clinical Emergency Hospital, 12 Revoluției din 1989 Bd., 300040 Timisoara, Romania
| | - Iulia-Maria Zbîrcea
- Department of Automation and Applied Informatics, “Politehnica” University of Timisoara, 300006 Timișoara, Romania
| | - Bogdan Hirtie
- ENT Department, “Victor Babes” University of Medicine and Pharmacy, 300042 Timișoara, Romania
| | - Cristina Uța
- Center of Immuno-Physiology and Biotechnologies, Department of Functional Sciences, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (R.-I.Z.)
- Timis County Emergency Clinical Hospital “Pius Brinzeu”, 156 Liviu Rebreanu Bd., 300723 Timisoara, Romania
| | - Camelia-Felicia Bănărescu
- Center of Immuno-Physiology and Biotechnologies, Department of Functional Sciences, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (R.-I.Z.)
- Timis County Emergency Clinical Hospital “Pius Brinzeu”, 156 Liviu Rebreanu Bd., 300723 Timisoara, Romania
| | - Carmen Panaitescu
- Center of Immuno-Physiology and Biotechnologies, Department of Functional Sciences, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (R.-I.Z.)
- Research Center for Gene and Cellular Therapies in the Treatment of Cancer—OncoGen, Timis County Emergency Clinical Hospital “Pius Brinzeu”, 156 Liviu Rebreanu Bd., 300723 Timisoara, Romania
- Timis County Emergency Clinical Hospital “Pius Brinzeu”, 156 Liviu Rebreanu Bd., 300723 Timisoara, Romania
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Forkan CP, Shrestha A, Yu A, Chuang C, Pociot F, Yarani R. Could hypoxic conditioning augment the potential of mesenchymal stromal cell-derived extracellular vesicles as a treatment for type 1 diabetes? Stem Cell Res Ther 2025; 16:37. [PMID: 39901225 PMCID: PMC11792614 DOI: 10.1186/s13287-025-04153-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Accepted: 01/16/2025] [Indexed: 02/05/2025] Open
Abstract
Type1 Diabetes (T1D) is an autoimmune disorder characterised by the loss of pancreatic β-cells. This β cell loss occurs primarily through inflammatory pathways culminating in apoptosis. Mesenchymal stromal cells (MSCs) have been heavily studied for therapeutic applications due to their regenerative, anti-apoptotic, immunomodulatory, and anti-inflammatory properties. The therapeutic effects of MSCs are mediated through cell-to-cell contact, differentiation, and the release of paracrine factors, which include the release of extracellular vesicles (EVs). Culturing MSCs in hypoxia, a low oxygen tension state more analogous to their physiological environment, seems to increase the therapeutic efficacy of MSC cell therapy, enhancing their immunomodulatory, anti-inflammatory, and anti-fibrotic properties. This is also the case with MSC-derived EVs, which show altered properties based on the parent cell preconditioning. In this review, we examine the evidence supporting the potential application of hypoxic preconditioning in strengthening MSC-EVs for treating the inflammatory and apoptotic causes of β cell loss in T1D.
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Affiliation(s)
- Cathal Patrick Forkan
- Translational Type 1 Diabetes Research, Department of Clinical and Translational Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Aruna Shrestha
- Translational Type 1 Diabetes Research, Department of Clinical and Translational Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Alfred Yu
- Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University School of Medicine, Palo Alto, CA, 94304, USA
| | - Christine Chuang
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Flemming Pociot
- Translational Type 1 Diabetes Research, Department of Clinical and Translational Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Reza Yarani
- Translational Type 1 Diabetes Research, Department of Clinical and Translational Research, Steno Diabetes Center Copenhagen, Herlev, Denmark.
- Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University School of Medicine, Palo Alto, CA, 94304, USA.
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Liang X, Tian S, Zhang H, Sun S, Zhang P, Li J, Li Y, Zhang Y, Liu Z. Efferocytosis: A new star of atherosclerotic plaques reversal. Int Immunopharmacol 2025; 146:113904. [PMID: 39724733 DOI: 10.1016/j.intimp.2024.113904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 12/16/2024] [Accepted: 12/16/2024] [Indexed: 12/28/2024]
Abstract
Efferocytosis is considered the key to eliminate apoptotic cells (ACs) under physiological and pathological conditions in vivo, mainly through different types of macrophages to achieve this process. Especially, tissue-resident macrophages (TRMs) are very significant for inflammation regression and maintenance of homeostasis in vivo. Abnormal efferocytosis will lead to the accumulation of ACs and the release of a variety of pro-inflammatory factors, which mediates the occurrence of many inflammatory diseases, including atherosclerosis (AS). AS is a chronic inflammatory vascular disease with the participation of the immune system. Defective efferocytosis will accelerate the progress of AS to a certain extent. Therefore, it is of great significance to understand the mechanism of efferocytosis and realize the prevention and treatment of AS through efferocytosis. In this review, we will briefly describe the specific process of efferocytosis, deeply discuss the possible molecular mechanism of impaired efferocytosis promoting the development of AS, and summarize the ways to prevent and treat AS through efferocytosis intervention therapy.
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Affiliation(s)
- Xiangyu Liang
- College of Pharmaceutical Sciences, Key Laboratory of Pharmaceutical Quality Control of Hebei Province, Hebei University, Baoding, China; State Key Laboratory of New Pharmaceutical Preparations and Excipients, Baoding, China.
| | - Shuoqi Tian
- College of Pharmaceutical Sciences, Key Laboratory of Pharmaceutical Quality Control of Hebei Province, Hebei University, Baoding, China; State Key Laboratory of New Pharmaceutical Preparations and Excipients, Baoding, China.
| | - Han Zhang
- College of Pharmaceutical Sciences, Key Laboratory of Pharmaceutical Quality Control of Hebei Province, Hebei University, Baoding, China; State Key Laboratory of New Pharmaceutical Preparations and Excipients, Baoding, China.
| | - Shusen Sun
- College of Pharmaceutical Sciences, Key Laboratory of Pharmaceutical Quality Control of Hebei Province, Hebei University, Baoding, China; State Key Laboratory of New Pharmaceutical Preparations and Excipients, Baoding, China.
| | - Peixiang Zhang
- College of Pharmaceutical Sciences, Key Laboratory of Pharmaceutical Quality Control of Hebei Province, Hebei University, Baoding, China; State Key Laboratory of New Pharmaceutical Preparations and Excipients, Baoding, China.
| | - Jiameng Li
- College of Pharmaceutical Sciences, Key Laboratory of Pharmaceutical Quality Control of Hebei Province, Hebei University, Baoding, China; State Key Laboratory of New Pharmaceutical Preparations and Excipients, Baoding, China.
| | - Yong Li
- Beijing Yongkang Nian Health Technology Co., Ltd., Beijing, China.
| | - Yanfen Zhang
- Technology Transfer Center, Hebei University, Baoding, China.
| | - Zhongcheng Liu
- College of Pharmaceutical Sciences, Key Laboratory of Pharmaceutical Quality Control of Hebei Province, Hebei University, Baoding, China; State Key Laboratory of New Pharmaceutical Preparations and Excipients, Baoding, China.
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Euler G, Parahuleva M. Monocytic microRNAs-Novel targets in atherosclerosis therapy. Br J Pharmacol 2025; 182:206-219. [PMID: 38575391 DOI: 10.1111/bph.16367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 02/02/2024] [Accepted: 02/16/2024] [Indexed: 04/06/2024] Open
Abstract
Atherosclerosis is a chronic proinflammatory disease of the vascular wall resulting in narrowing of arteries due to plaque formation, thereby causing reduced blood supply that is the leading cause for diverse end-organ damage with high mortality rates. Monocytes/macrophages, activated by elevated circulating lipoproteins, are significantly involved in the formation and development of atherosclerotic plaques. The imbalance between proinflammatory and anti-inflammatory macrophages, arising from dysregulated macrophage polarization, appears to be a driving force in this process. Proatherosclerotic processes acting on monocytes/macrophages include accumulation of cholesterol in macrophages leading to foam cell formation, as well as dysfunctional efferocytosis, all of which contribute to the formation of unstable plaques. In recent years, microRNAs (miRs) were identified as factors that could modulate monocyte/macrophage function and may therefore interfere with the atherosclerotic process. In this review, we present effects of monocyte/macrophage-derived miRs on atherosclerotic processes in order to reveal new treatment options using miRmimics or antagomiRs. LINKED ARTICLES: This article is part of a themed issue Non-coding RNA Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.2/issuetoc.
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Affiliation(s)
- Gerhild Euler
- Institute of Physiology, Justus Liebig University, Giessen, Germany
| | - Mariana Parahuleva
- Internal Medicine/Cardiology and Angiology, University Hospital of Giessen and Marburg, Marburg, Germany
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Sopić M, Vladimirov S, Munjas J, Mitić T, Hall IF, Jusic A, Ruzic D, Devaux Y. Targeting noncoding RNAs to treat atherosclerosis. Br J Pharmacol 2025; 182:220-245. [PMID: 38720437 DOI: 10.1111/bph.16412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 03/06/2024] [Accepted: 04/05/2024] [Indexed: 12/13/2024] Open
Abstract
Noncoding RNAs (ncRNAs) are pivotal for various pathological processes, impacting disease progression. The potential for leveraging ncRNAs to prevent or treat atherosclerosis and associated cardiovascular diseases is of great significance, especially given the increasing prevalence of atherosclerosis in an ageing and sedentary population. Together, these diseases impose a substantial socio-economic burden, demanding innovative therapeutic solutions. This review explores the potential of ncRNAs in atherosclerosis treatment. We commence by examining approaches for identifying and characterizing atherosclerosis-associated ncRNAs. We then delve into the functional aspects of ncRNAs in atherosclerosis development and progression. Additionally, we review current RNA and RNA-targeting molecules in development or under approval for clinical use, offering insights into their pharmacological potential. The importance of improved ncRNA delivery strategies is highlighted. Finally, we suggest avenues for advanced research to accelerate the use of ncRNAs in treating atherosclerosis and mitigating its societal impact. LINKED ARTICLES: This article is part of a themed issue Non-coding RNA Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.2/issuetoc.
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Affiliation(s)
- Miron Sopić
- Cardiovascular Research Unit, Department of Precision Health, Luxembourg Institute of Health, Luxembourg, Luxembourg
- Department of Medical Biochemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
| | - Sandra Vladimirov
- Department of Medical Biochemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
| | - Jelena Munjas
- Department of Medical Biochemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
| | - Tijana Mitić
- BHF/University Centre for Cardiovascular Science, Queens Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Ignacio Fernando Hall
- BHF/University Centre for Cardiovascular Science, Queens Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Amela Jusic
- HAYA Therapeutics SA, SuperLab Suisse - Bâtiment Serine, Lausanne, Vaud, Switzerland
| | - Dusan Ruzic
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
| | - Yvan Devaux
- Cardiovascular Research Unit, Department of Precision Health, Luxembourg Institute of Health, Luxembourg, Luxembourg
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Al-Attabi A, Mukhlif BA, Al-Shami KR, Merza MS, Alkubaisy SA, Abdulhadi MA. Evaluation of the effect of taurine on the matrix metalloproteinase-9 and the expression changes of miRNA-21 and miRNA-146a in SH-SY5Y cell line. Horm Mol Biol Clin Investig 2024; 45:165-170. [PMID: 39277808 DOI: 10.1515/hmbci-2024-0005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Accepted: 07/23/2024] [Indexed: 09/17/2024]
Abstract
OBJECTIVES Alzheimer's disease (AD), a brain disorder, is the leading cause of dementia among older adults. Taurine, an amino acid abundantly present in the brain, and shows potential neuroprotective properties. Therefore, we investigated the effects of taurine on Matrix Metalloproteinase-9 (MMP-9) levels and the expression changes of miRNA-21 and miRNA-146a in the SH-SY5Y cell line. METHODS Taurine's impact on the SH-SY5Y cell line was evaluated via the 2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. MMP-9 levels were measured using an enzyme-linked immunosorbent assay (ELISA) kit, while the expression of miRNA-21 and miRNA-146a genes was assessed through Real-Time PCR analysis. RESULTS The MTT assay revealed no toxic effects on SH-SY5Y cells with increasing concentrations of taurine. Analysis of gene expression indicated a rise in miRNA-21 expression and a decline in miRNA-146 expression with increasing taurine concentration, with the most notable change observed at 1 mg/mL taurine (p<0.001). ELISA results demonstrated a significant increase in MMP-9 levels in the SH-SY5Y cell line treated with 1 mg/mL taurine compared to the untreated group (p<0.001). CONCLUSIONS Our study revealed that taurine can alter the expression of miRNA-146a and miRNA-21. In conclusion, taurine therapy presents promising therapeutic avenues for treating AD or mitigating severe symptoms. Nonetheless, further research is necessary to comprehensively grasp the precise mechanisms at play.
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Affiliation(s)
| | - Bilal Abdulmajeed Mukhlif
- Department of Medical Laboratories Techniques, College of Health and Medical Technology, University of Al Maarif, Al Anbar, Iraq
| | - Karrar R Al-Shami
- Department of Forensic Sciences, College of Science, National University of Science and Technology, Dhi Qar, Iraq
| | - Muna S Merza
- Prosthetic Dental Techniques Department, Al-Mustaqbal, University College, Hillah, Babylon, Iraq
| | | | - Mohanad Ali Abdulhadi
- Department of Biochemistry, College of Medicine, University of Anbar, Ramadi City, Al-Anbar Governorate, Iraq
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Rawal S, Randhawa V, Rizvi SHM, Sachan M, Wara AK, Pérez-Cremades D, Weisbrod RM, Hamburg NM, Feinberg MW. miR-369-3p ameliorates diabetes-associated atherosclerosis by regulating macrophage succinate-GPR91 signalling. Cardiovasc Res 2024; 120:1693-1712. [PMID: 38703377 PMCID: PMC11587565 DOI: 10.1093/cvr/cvae102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 03/04/2024] [Accepted: 05/02/2024] [Indexed: 05/06/2024] Open
Abstract
AIMS Diabetes leads to dysregulated macrophage immunometabolism, contributing to accelerated atherosclerosis progression. Identifying critical factors to restore metabolic alterations and promote resolution of inflammation remains an unmet goal. MicroRNAs orchestrate multiple signalling events in macrophages, yet their therapeutic potential in diabetes-associated atherosclerosis remains unclear. METHODS AND RESULTS miRNA profiling revealed significantly lower miR-369-3p expression in aortic intimal lesions from Ldlr-/- mice on a high-fat sucrose-containing (HFSC) diet for 12 weeks. miR-369-3p was also reduced in peripheral blood mononuclear cells from diabetic patients with coronary artery disease (CAD). Cell-type expression profiling showed miR-369-3p enrichment in aortic macrophages. In vitro, oxLDL treatment reduced miR-369-3p expression in mouse bone marrow-derived macrophages (BMDMs). Metabolic profiling in BMDMs revealed that miR-369-3p overexpression blocked the oxidized low density lipoprotein (oxLDL)-mediated increase in the cellular metabolite succinate and reduced mitochondrial respiration (OXPHOS) and inflammation [Interleukin (lL)-1β, TNF-α, and IL-6]. Mechanistically, miR-369-3p targeted the succinate receptor (GPR91) and alleviated the oxLDL-induced activation of inflammasome signalling pathways. Therapeutic administration of miR-369-3p mimics in HFSC-fed Ldlr-/- mice reduced GPR91 expression in lesional macrophages and diabetes-accelerated atherosclerosis, evident by a decrease in plaque size and pro-inflammatory Ly6Chi monocytes. RNA-Seq analyses showed more pro-resolving pathways in plaque macrophages from miR-369-3p-treated mice, consistent with an increase in macrophage efferocytosis in lesions. Finally, a GPR91 antagonist attenuated oxLDL-induced inflammation in primary monocytes from human subjects with diabetes. CONCLUSION These findings establish a therapeutic role for miR-369-3p in halting diabetes-associated atherosclerosis by regulating GPR91 and macrophage succinate metabolism.
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MESH Headings
- Animals
- MicroRNAs/metabolism
- MicroRNAs/genetics
- Receptors, G-Protein-Coupled/metabolism
- Receptors, G-Protein-Coupled/genetics
- Macrophages/metabolism
- Macrophages/pathology
- Signal Transduction
- Humans
- Mice, Knockout
- Atherosclerosis/metabolism
- Atherosclerosis/pathology
- Atherosclerosis/genetics
- Male
- Mice, Inbred C57BL
- Disease Models, Animal
- Lipoproteins, LDL/metabolism
- Succinic Acid/metabolism
- Plaque, Atherosclerotic
- Mice
- Receptors, LDL/genetics
- Receptors, LDL/deficiency
- Receptors, LDL/metabolism
- Aortic Diseases/pathology
- Aortic Diseases/metabolism
- Aortic Diseases/genetics
- Aortic Diseases/prevention & control
- Aortic Diseases/immunology
- Cells, Cultured
- Gene Expression Regulation
- Diabetic Angiopathies/metabolism
- Diabetic Angiopathies/genetics
- Diabetic Angiopathies/pathology
- Diabetic Angiopathies/prevention & control
- Female
- Middle Aged
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Affiliation(s)
- Shruti Rawal
- Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
| | - Vinay Randhawa
- Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
| | - Syed Husain Mustafa Rizvi
- Vascular Biology Section, Boston University School of Medicine, Boston, MA, USA
- Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA
| | - Madhur Sachan
- Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
| | - Akm Khyrul Wara
- Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
| | - Daniel Pérez-Cremades
- Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
- Department of Physiology, University of Valencia, INCLIVA Biomedical Research Institute, Valencia 46010, Spain
| | - Robert M Weisbrod
- Vascular Biology Section, Boston University School of Medicine, Boston, MA, USA
- Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA
| | - Naomi M Hamburg
- Vascular Biology Section, Boston University School of Medicine, Boston, MA, USA
- Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA
| | - Mark W Feinberg
- Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
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10
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Nazir A, Uwishema O, Shariff S, Franco WXG, El Masri N, Ayele ND, Munyangaju I, Alzain FE, Wojtara M. A Thorough Navigation of miRNA's Blueprint in Crafting Cardiovascular Fate. Health Sci Rep 2024; 7:e70136. [PMID: 39502130 PMCID: PMC11535861 DOI: 10.1002/hsr2.70136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Revised: 09/20/2024] [Accepted: 09/25/2024] [Indexed: 11/08/2024] Open
Abstract
Introduction Cardiovascular diseases contribute significantly to global morbidity and mortality. MicroRNAs are crucial in the development and progression of these diseases by regulating gene expression in various cells and tissues. Their roles in conditions like atherosclerosis, heart failure, myocardial infarction, and arrhythmias have been widely researched. Materials and Methods The present study provides an overview of existing evidence regarding miRNAs' role in cardiovascular disease pathogenesis. Furthermore, the study examines current state-of-the-art technologies used in the study of miRNAs in cardiovascular disease. As a final point, we examine how miRNAs may serve as disease biomarkers, therapeutic targets, and prognostic indicators. Results In cardiology, microRNAs, small noncoding RNA molecules, are crucial to the posttranscriptional regulation of genes. Their role in regulating cardiac cell differentiation and maturation is critical during the development of the heart. They maintain the cardiac function of an adult heart by contributing to its electrical and contractile activity. By binding to messenger RNA molecules, they inhibit protein translation or degrade mRNA. Several cardiovascular diseases are associated with dysregulation of miRNAs, including arrhythmias, hypertension, atherosclerosis, and heart failure. miRNAs can be used as biomarkers to diagnose and predict diseases as well as therapeutic targets. A variety of state-of-the-art technologies have aided researchers in discovering, profiling, and analyzing miRNAs, including microarray analysis, next-generation sequencing, and others. Conclusion Developing new diagnostics and therapeutic approaches is becoming more feasible as researchers refine their understanding of miRNA function. Ultimately, this will reduce the burden of cardiovascular disease around the world.
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Affiliation(s)
- Abubakar Nazir
- Department of MedicineOli Health Magazine Organization, Research and EducationKigaliRwanda
- Department of MedicineKing Edward Medical UniversityPakistan
| | - Olivier Uwishema
- Department of MedicineOli Health Magazine Organization, Research and EducationKigaliRwanda
| | - Sanobar Shariff
- Department of MedicineOli Health Magazine Organization, Research and EducationKigaliRwanda
- Department of MedicineYerevan State Medical UniversityYerevanArmenia
| | - William Xochitun Gopar Franco
- Department of MedicineOli Health Magazine Organization, Research and EducationKigaliRwanda
- Department of MedicineUniversity of GuadalajaraGuadalajaraMexico
| | - Noha El Masri
- Department of MedicineOli Health Magazine Organization, Research and EducationKigaliRwanda
- Faculty of MedicineBeirut Arab UniversityLebanon
| | - Nitsuh Dejene Ayele
- Department of MedicineOli Health Magazine Organization, Research and EducationKigaliRwanda
- Department of Internal Medicine, Faculty of MedicineWolkite UniversityWolkiteEthiopia
| | - Isabelle Munyangaju
- Department of MedicineOli Health Magazine Organization, Research and EducationKigaliRwanda
- Barcelona Institute for Global Health—Hospital ClínicUniversitat de Barcelona
| | - Fatima Esam Alzain
- Department of MedicineOli Health Magazine Organization, Research and EducationKigaliRwanda
- Department of MedicineCollege of Medicine and General Surgery—Sudan University of Science and Technology
| | - Magda Wojtara
- Department of MedicineOli Health Magazine Organization, Research and EducationKigaliRwanda
- Department of MedicineUniversity of Michigan Medical SchoolAnn ArborMichiganUSA
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11
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Yin Y, Tian N, Deng Z, Wang J, Kuang L, Tang Y, Zhu S, Dong Z, Wang Z, Wu X, Han M, Hu X, Deng Y, Yin T, Wang Y. Targeted Microglial Membrane-Coated MicroRNA Nanosponge Mediates Inhibition of Glioblastoma. ACS NANO 2024; 18:29089-29105. [PMID: 39393070 DOI: 10.1021/acsnano.4c10509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/13/2024]
Abstract
Glioblastoma (GBM) is the most prevalent primary brain tumor. Recent research emphasizes the crucial role of microRNAs (miRs) in GBM pathogenesis, and targeting miRs offers an effective approach for precise GBM therapy. However, inhibiting a single miR may not be sufficient due to the compensatory mechanisms of GBM. Herein, we developed a miR-nanosponge capable of specifically capturing multiple miRs involved in tumor growth, migration, invasion, angiogenesis, and the creation of an immunosuppressive microenvironment, thereby offering a comprehensive treatment for GBM. Coated with BV2 cell membrane (BM) for enhanced blood-brain barrier (BBB) crossing and GBM targeting, the BM@miR-nanosponge targets miR-9, miR-21, miR-215, and miR-221, significantly inhibiting GBM progression and modulating the immune system for a thorough GBM eradication. The BM@miR-nanosponge notably extended the median survival time of GBM-bearing mice and outperformed the standard treatment drug temozolomide (TMZ). This study introduces a comprehensive miR-based strategy for GBM treatment and highlights the importance of targeting multiple miRs associated with tumor survival for effective therapy.
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Affiliation(s)
- Ying Yin
- School of Medicine, Chongqing University, Chongqing 400030, China
- Department of Neurosurgery, Chongqing University Central Hospital & Chongqing Emergency Medical Center, Chongqing University, Chongqing 400014, China
| | - Nixin Tian
- School of Medicine, Chongqing University, Chongqing 400030, China
| | - Zhiqin Deng
- School of Medicine, Chongqing University, Chongqing 400030, China
| | - Jiaojiao Wang
- School of Medicine, Chongqing University, Chongqing 400030, China
| | - Lei Kuang
- School of Medicine, Chongqing University, Chongqing 400030, China
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China
| | - Yuanyang Tang
- School of Medicine, Chongqing University, Chongqing 400030, China
| | - Siqing Zhu
- School of Medicine, Chongqing University, Chongqing 400030, China
| | - Zhufeng Dong
- School of Medicine, Chongqing University, Chongqing 400030, China
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China
| | - Zheng Wang
- School of Medicine, Chongqing University, Chongqing 400030, China
| | - Xinxia Wu
- School of Medicine, Chongqing University, Chongqing 400030, China
| | - Mengwei Han
- School of Medicine, Chongqing University, Chongqing 400030, China
| | - Xiaoye Hu
- School of Medicine, Chongqing University, Chongqing 400030, China
| | - Yongbing Deng
- Department of Neurosurgery, Chongqing University Central Hospital & Chongqing Emergency Medical Center, Chongqing University, Chongqing 400014, China
| | - Tieying Yin
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China
| | - Yazhou Wang
- School of Medicine, Chongqing University, Chongqing 400030, China
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12
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Kim EH, Choi J, Jang H, Kim Y, Lee JW, Ryu Y, Choi J, Choi Y, Chi SG, Kwon IC, Yang Y, Kim SH. Targeted delivery of anti-miRNA21 sensitizes PD-L1 high tumor to immunotherapy by promoting immunogenic cell death. Theranostics 2024; 14:3777-3792. [PMID: 38994018 PMCID: PMC11234275 DOI: 10.7150/thno.97755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Accepted: 06/05/2024] [Indexed: 07/13/2024] Open
Abstract
Rationale: Growing evidence has demonstrated that miRNA-21 (miR-21) upregulation is closely associated with tumor pathogenesis. However, the mechanisms by which miR-21 inhibition modulates the immunosuppressive tumor microenvironment (TME) and improves tumor sensitivity to immune checkpoint blockade therapies remain largely unexplored. In this study, we demonstrate the precise delivery of anti-miR-21 using a PD-L1-targeting peptide conjugate (P21) to the PD-L1high TME. Methods: Investigating miR-21 inhibition mechanisms involved conducting quantitative real-time PCR, western blot, flow cytometry, and confocal microscopy analyses. The antitumor efficacy and immune profile of P21 monotherapy, or combined with anti-PD-L1 immune checkpoint inhibitors, were assessed in mouse models bearing CT26.CL25 tumors and 4T1 breast cancer. Results Inhibition of oncogenic miR-21 in cancer cells by P21 efficiently activates tumor suppressor genes, inducing autophagy and endoplasmic reticulum stress. Subsequent cell-death-associated immune activation (immunogenic cell death) is initiated via the release of damage-associated molecular patterns. The in vivo results also illustrated that the immunogenic cell death triggered by P21 could effectively sensitize the immunosuppressive TME. That is, P21 enhances CD8+ T cell infiltration in tumor tissues by conferring immunogenicity to dying cancer cells and promoting dendritic cell maturation. Meanwhile, combining P21 with an anti-PD-L1 immune checkpoint inhibitor elicits a highly potent antitumor effect in a CT26.CL25 tumor-bearing mouse model and 4T1 metastatic tumor model. Conclusions: Collectively, we have clarified a miR-21-related immunogenic cell death mechanism through the precise delivery of anti-miR-21 to the PD-L1high TME. These findings highlight the potential of miR-21 as a target for immunotherapeutic interventions.
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Affiliation(s)
- Eun Hye Kim
- Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
- Department of Life Sciences, Korea University, Seoul 02841, Republic of Korea
| | - Jiwoong Choi
- Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
| | - Hochung Jang
- Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
- Division of Bio-Medical Science and Technology, KIST School, University of Science and Technology, Seoul 02792, Republic of Korea
| | - Yelee Kim
- Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
- Department of Life Sciences, Korea University, Seoul 02841, Republic of Korea
| | - Jong Won Lee
- Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea
| | - Youngri Ryu
- Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
- Department of Life Sciences, Korea University, Seoul 02841, Republic of Korea
| | - Jiwon Choi
- Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
- Department of Bioengineering, Korea University, Seoul 02841, Republic of Korea
| | - Yeonho Choi
- Department of Bioengineering, Korea University, Seoul 02841, Republic of Korea
| | - Sung-Gil Chi
- Department of Life Sciences, Korea University, Seoul 02841, Republic of Korea
| | - Ick Chan Kwon
- Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea
| | - Yoosoo Yang
- Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
- Division of Bio-Medical Science and Technology, KIST School, University of Science and Technology, Seoul 02792, Republic of Korea
| | - Sun Hwa Kim
- Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea
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13
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Almohaimeed HM, Almars AI, Alsulaimani F, Basri AM, Althobaiti NA, Albalaw AE, Alsharif I, Al Abdulmonem W, Hershan AA, Soliman MH. Investigating the potential neuroprotective benefits of taurine and Dihydrotestosterone and Hydroxyprogesterone levels in SH-SY5Y cells. Front Aging Neurosci 2024; 16:1379431. [PMID: 38867846 PMCID: PMC11168113 DOI: 10.3389/fnagi.2024.1379431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Accepted: 04/05/2024] [Indexed: 06/14/2024] Open
Abstract
Background Taurine, an amino acid abundantly found in the brain and other tissues, has potential neuroprotective properties. Alzheimer's disease (AD) is a commonly occurring type of dementia, which becomes more prevalent as people age. This experiment aimed to assess the neuroprotective effects of taurine on SH-SY5Y cells by examining its impact on Dihydrotestosterone (DHT), Dihydroprogesterone (DHP), as well as the expression of miRNA-21 and miRNA-181. Methods The effects of various taurine concentrations (0.25, and 0.75 mg/mL), and LPS (0.1, and 12 mg/mL) on the SH-SY5Y cell line were assessed using the MTT assay. The levels of DHT and DHP were quantified using an ELISA kit. Additionally, the expression levels of miRNA-181 and miRNA-21 genes were examined through Real-Time PCR analysis. Results The results of the MTT assay showed that treatment with taurine at concentrations of 0.25, and 0.75 mg/mL reduces the toxicity of LPS in SH-SY5Y cells. ELISA results indicated that taurine at a concentration of 0.25, and 0.75 mg/mL significantly elevated DHT and DHP hormones in the SH-SY5Y cell line compared to the untreated group (p < 0.01). The expression levels of IL-1β and IL-6 were decreased under the influence of LPS in SH-SY5Y cells after taurine treatment (p < 0.01). Gene expression analysis revealed that increasing taurine concentration resulted in heightened expression of miRNA-181 and miRNA-21, with the most significant increase observed at a concentration of 0.75 mg/mL (p < 0.001). Conclusion Our study findings revealed that the expression of miRNA-181 and miRNA-21 can be enhanced by taurine. Consequently, exploring the targeting of taurine, miRNA-181, and miRNA-21 or considering hormone therapy may offer potential therapeutic approaches for treating AD or alleviating severe symptoms. Nonetheless, in order to fully comprehend the precise mechanisms involved, additional research is required.
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Affiliation(s)
- Hailah M. Almohaimeed
- Department of Basic Science, College of Medicine, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Amany I. Almars
- Department of Medial Laboratory Sciences, Faculty of Applied Medical Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Fayez Alsulaimani
- Department of Medial Laboratory Sciences, Faculty of Applied Medical Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Ahmed M. Basri
- Department of Medial Laboratory Sciences, Faculty of Applied Medical Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Norah A. Althobaiti
- Biology Department, College of Science and Humanities Al Quwaiiyah, Shaqra University, Al Quwaiiyah, Saudi Arabia
| | - Aishah E. Albalaw
- Department of Biology, Faculty of Science, University of Tabuk, Tabuk, Saudi Arabia
| | - Ifat Alsharif
- Department of Biology, Jamoum University College, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Waleed Al Abdulmonem
- Department of Pathology, College of Medicine, Qassim University, Buraidah, Saudi Arabia
| | - Almonther Abdullah Hershan
- Department of Medical Microbiology and Parasitology, College of Medicine, The University of Jeddah, Jeddah, Saudi Arabia
| | - Mona H. Soliman
- Botany and Microbiology Department, Faculty of Science, Cairo University, Giza, Egypt
- Biology Department, Faculty of Science, Taibah University, Yanbu, Saudi Arabia
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14
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Xin C, He W, Sun X, Li M, Wang H. The Association of Micro-RNA 21 and Hypertension: A Meta-Analysis. Glob Heart 2024; 19:41. [PMID: 38708403 PMCID: PMC11067968 DOI: 10.5334/gh.1325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 04/16/2024] [Indexed: 05/07/2024] Open
Abstract
Hypertension is a multifactorial, complex disease with high morbidity and mortality rates. Studies have found that micro-RNA 21 (miR-21) levels are significantly increased in patients with hypertension. However, other studies have reported opposite results. Therefore, the relationship between miR-21 expression and hypertension remains controversial. This meta-analysis was conducted to statistically evaluate the miR-21 levels of patients with hypertension. A literature research was conducted using Web of Science, Embase, PubMed, and CNKI. To search for titles or abstracts, 'hypertension' in combination with the terms 'miR-21,' 'microRNA-21,' or 'miRNA-21' were used as keywords. Standardized mean differences (SMD) with corresponding 95% confidence intervals (CIs) were determined from the results of the meta-analysis. In total, 12 articles were included in this meta-analysis, involving 546 cases and 436 controls. The results of the meta-analysis showed that miR-21 levels in patients with hypertension were significantly higher than those in the controls (SMD: 1.22; 95% CI [0.35, 2.09]). This meta-analysis is the first to evaluate miR-21 in patients with hypertension. MiR-21 may be a new target for the prediction and treatment of hypertension. Further high-quality studies are needed to better support the association between miR-21 and hypertension.
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Affiliation(s)
- Caihong Xin
- Department of Endocrinology and Metabolism, The Fourth People’s Hospital of Shenyang, Shenyang, P.R. China
| | - Wei He
- Department of Endocrinology and Metabolism, People’s Hospital of Liaoning Province, Shenyang, P.R. China
| | - Xin Sun
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Soochow University, Suzhou, P.R. China
| | - Mianxian Li
- Department of Cardiology, The First Affiliated Hospital of Soochow University, Suzhou, P.R. China
| | - Hongli Wang
- Department of Cardiology, The Second Affiliated Hospital of Dalian Medical University, Dalian, P.R. China
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15
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Parsamanesh N, Poudineh M, Siami H, Butler AE, Almahmeed W, Sahebkar A. RNA interference-based therapies for atherosclerosis: Recent advances and future prospects. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2023; 204:1-43. [PMID: 38458734 DOI: 10.1016/bs.pmbts.2023.12.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/10/2024]
Abstract
Atherosclerosis represents a pathological state that affects the arterial system of the organism. This chronic, progressive condition is typified by the accumulation of atheroma within arterial walls. Modulation of RNA molecules through RNA-based therapies has expanded the range of therapeutic options available for neurodegenerative diseases, infectious diseases, cancer, and, more recently, cardiovascular disease (CVD). Presently, microRNAs and small interfering RNAs (siRNAs) are the most widely employed therapeutic strategies for targeting RNA molecules, and for regulating gene expression and protein production. Nevertheless, for these agents to be developed into effective medications, various obstacles must be overcome, including inadequate binding affinity, instability, challenges of delivering to the tissues, immunogenicity, and off-target toxicity. In this comprehensive review, we discuss in detail the current state of RNA interference (RNAi)-based therapies.
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Affiliation(s)
- Negin Parsamanesh
- Department of Genetics and Molecular Medicine, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Mohadeseh Poudineh
- Student Research Committee, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Haleh Siami
- School of Medicine, Islamic Azad University of Medical Science, Tehran, Iran
| | - Alexandra E Butler
- Research Department, Royal College of Surgeons in Ireland, Bahrain, Adliya, Bahrain
| | - Wael Almahmeed
- Heart and Vascular Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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16
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Iusupova AO, Pakhtusov NN, Slepova OA, Belenkov YN, Privalova EV, Bure IV, Vetchinkina EA, Nemtsova MV. MiRNA-21a, miRNA-145, and miRNA-221 Expression and Their Correlations with WNT Proteins in Patients with Obstructive and Non-Obstructive Coronary Artery Disease. Int J Mol Sci 2023; 24:17613. [PMID: 38139440 PMCID: PMC10744268 DOI: 10.3390/ijms242417613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 12/08/2023] [Accepted: 12/16/2023] [Indexed: 12/24/2023] Open
Abstract
MicroRNAs and the WNT signaling cascade regulate the pathogenetic mechanisms of atherosclerotic coronary artery disease (CAD) development. OBJECTIVE To evaluate the expression of microRNAs (miR-21a, miR-145, and miR-221) and the role of the WNT signaling cascade (WNT1, WNT3a, WNT4, and WNT5a) in obstructive CAD and ischemia with no obstructive coronary arteries (INOCA). METHOD The cross-sectional observational study comprised 94 subjects. The expression of miR-21a, miR-145, miR-221 (RT-PCR) and the protein levels of WNT1, WNT3a, WNT4, WNT5a, LRP6, and SIRT1 (ELISA) were estimated in the plasma of 20 patients with INOCA (66.5 [62.8; 71.2] years; 25% men), 44 patients with obstructive CAD (64.0 [56.5; 71,0] years; 63.6% men), and 30 healthy volunteers without risk factors for cardiovascular diseases (CVD). RESULTS Higher levels of WNT1 (0.189 [0.184; 0.193] ng/mL vs. 0.15 [0.15-0.16] ng/mL, p < 0.001) and WNT3a (0.227 [0.181; 0.252] vs. 0.115 [0.07; 0.16] p < 0.001) were found in plasma samples from patients with obstructive CAD, whereas the INOCA group was characterized by higher concentrations of WNT4 (0.345 [0.278; 0.492] ng/mL vs. 0.203 [0.112; 0.378] ng/mL, p = 0.025) and WNT5a (0.17 [0.16; 0.17] ng/mL vs. 0.01 [0.007; 0.018] ng/mL, p < 0.001). MiR-221 expression level was higher in all CAD groups compared to the control group (p < 0.001), whereas miR-21a was more highly expressed in the control group than in the obstructive (p = 0.012) and INOCA (p = 0.003) groups. Correlation analysis revealed associations of miR-21a expression with WNT1 (r = -0.32; p = 0.028) and SIRT1 (r = 0.399; p = 0.005) protein levels in all CAD groups. A positive correlation between miR-145 expression and the WNT4 protein level was observed in patients with obstructive CAD (r = 0.436; p = 0.016). Based on multivariate regression analysis, a mathematical model was constructed that predicts the type of coronary lesion. WNT3a and LRP6 were the independent predictors of INOCA (p < 0.001 and p = 0.002, respectively). CONCLUSIONS Activation of the canonical cascade of WNT-β-catenin prevailed in patients with obstructive CAD, whereas in the INOCA and control groups, the activity of the non-canonical pathway was higher. It can be assumed that miR-21a has a negative effect on the formation of atherosclerotic CAD. Alternatively, miR-145 could be involved in the development of coronary artery obstruction, presumably through the regulation of the WNT4 protein. A mathematical model with WNT3a and LRP6 as predictors allows for the prediction of the type of coronary artery lesion.
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Affiliation(s)
- Alfiya Oskarovna Iusupova
- Department of Hospital Therapy No 1, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia (O.A.S.); (Y.N.B.)
| | - Nikolay Nikolaevich Pakhtusov
- Department of Hospital Therapy No 1, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia (O.A.S.); (Y.N.B.)
| | - Olga Alexandrovna Slepova
- Department of Hospital Therapy No 1, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia (O.A.S.); (Y.N.B.)
| | - Yuri Nikitich Belenkov
- Department of Hospital Therapy No 1, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia (O.A.S.); (Y.N.B.)
| | - Elena Vitalievna Privalova
- Department of Hospital Therapy No 1, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia (O.A.S.); (Y.N.B.)
| | - Irina Vladimirovna Bure
- Laboratory of Medical Genetics, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (I.V.B.); (E.A.V.); (M.V.N.)
- Research Institute of Molecular and Personalized Medicine, Russian Medical Academy of Continuous Professional Education, 125445 Moscow, Russia
| | - Ekaterina Alexandrovna Vetchinkina
- Laboratory of Medical Genetics, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (I.V.B.); (E.A.V.); (M.V.N.)
| | - Marina Vyacheslavovna Nemtsova
- Laboratory of Medical Genetics, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (I.V.B.); (E.A.V.); (M.V.N.)
- Laboratory of Epigenetics, Research Centre for Medical Genetics, 115522 Moscow, Russia
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Chaube B, Citrin KM, Sahraei M, Singh AK, de Urturi DS, Ding W, Pierce RW, Raaisa R, Cardone R, Kibbey R, Fernández-Hernando C, Suárez Y. Suppression of angiopoietin-like 4 reprograms endothelial cell metabolism and inhibits angiogenesis. Nat Commun 2023; 14:8251. [PMID: 38086791 PMCID: PMC10716292 DOI: 10.1038/s41467-023-43900-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 11/23/2023] [Indexed: 12/18/2023] Open
Abstract
Angiopoietin-like 4 (ANGPTL4) is known to regulate various cellular and systemic functions. However, its cell-specific role in endothelial cells (ECs) function and metabolic homeostasis remains to be elucidated. Here, using endothelial-specific Angptl4 knock-out mice (Angptl4iΔEC), and transcriptomics and metabolic flux analysis, we demonstrate that ANGPTL4 is required for maintaining EC metabolic function vital for vascular permeability and angiogenesis. Knockdown of ANGPTL4 in ECs promotes lipase-mediated lipoprotein lipolysis, which results in increased fatty acid (FA) uptake and oxidation. This is also paralleled by a decrease in proper glucose utilization for angiogenic activation of ECs. Mice with endothelial-specific deletion of Angptl4 showed decreased pathological neovascularization with stable vessel structures characterized by increased pericyte coverage and reduced permeability. Together, our study denotes the role of endothelial-ANGPTL4 in regulating cellular metabolism and angiogenic functions of EC.
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Affiliation(s)
- Balkrishna Chaube
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA
- Yale Center for Molecular and System Metabolism, Yale University School of Medicine, New Haven, CT, USA
| | - Kathryn M Citrin
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA
- Yale Center for Molecular and System Metabolism, Yale University School of Medicine, New Haven, CT, USA
- Department of Cellular & Molecular Physiology, Yale University, New Haven, CT, USA
| | - Mahnaz Sahraei
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Abhishek K Singh
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA
| | - Diego Saenz de Urturi
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA
- Yale Center for Molecular and System Metabolism, Yale University School of Medicine, New Haven, CT, USA
| | - Wen Ding
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Richard W Pierce
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA
- Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA
| | - Raaisa Raaisa
- Department of Internal Medicine, Yale University, New Haven, CT, USA
| | - Rebecca Cardone
- Department of Internal Medicine, Yale University, New Haven, CT, USA
| | - Richard Kibbey
- Yale Center for Molecular and System Metabolism, Yale University School of Medicine, New Haven, CT, USA
- Department of Cellular & Molecular Physiology, Yale University, New Haven, CT, USA
- Department of Internal Medicine, Yale University, New Haven, CT, USA
| | - Carlos Fernández-Hernando
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA
- Yale Center for Molecular and System Metabolism, Yale University School of Medicine, New Haven, CT, USA
- Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
| | - Yajaira Suárez
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA.
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA.
- Yale Center for Molecular and System Metabolism, Yale University School of Medicine, New Haven, CT, USA.
- Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
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Kim TJ, Kim YG, Jung W, Jang S, Ko HG, Park CH, Byun JS, Kim DY. Non-Coding RNAs as Potential Targets for Diagnosis and Treatment of Oral Lichen Planus: A Narrative Review. Biomolecules 2023; 13:1646. [PMID: 38002328 PMCID: PMC10669845 DOI: 10.3390/biom13111646] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 10/31/2023] [Accepted: 11/10/2023] [Indexed: 11/26/2023] Open
Abstract
Oral lichen planus (OLP) is a chronic inflammatory disease that is characterized by the infiltration of T cells into the oral mucosa, causing the apoptosis of basal keratinocytes. OLP is a multifactorial disease of unknown etiology and is not solely caused by the malfunction of a single key gene but rather by various intracellular and extracellular factors. Non-coding RNAs play a critical role in immunological homeostasis and inflammatory response and are found in all cell types and bodily fluids, and their expression is closely regulated to preserve normal physiologies. The dysregulation of non-coding RNAs may be highly implicated in the onset and progression of diverse inflammatory disorders, including OLP. This narrative review summarizes the role of non-coding RNAs in molecular and cellular changes in the oral epithelium during OLP pathogenesis.
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Affiliation(s)
- Tae-Jun Kim
- Department of Pharmacology, School of Dentistry, Kyungpook National University, Daegu 41940, Republic of Korea
| | - Yu Gyung Kim
- Department of Pharmacology, School of Dentistry, Kyungpook National University, Daegu 41940, Republic of Korea
| | - Won Jung
- Department of Oral Medicine, Institute of Oral Bioscience, School of Dentistry, Jeonbuk National University, Jeonju 54896, Republic of Korea
| | - Sungil Jang
- Department of Oral Biochemistry, Institute of Oral Bioscience, School of Dentistry, Jeonbuk National University, Jeonju 54896, Republic of Korea
| | - Hyoung-Gon Ko
- Department of Anatomy and Neurobiology, School of Dentistry, Kyungpook National University, Daegu 41940, Republic of Korea
| | - Chan Ho Park
- Department of Dental Biomaterials, School of Dentistry, Kyungpook National University, Daegu 41940, Republic of Korea
| | - Jin-Seok Byun
- Department of Oral Medicine, School of Dentistry, Kyungpook National University, Daegu 41940, Republic of Korea
| | - Do-Yeon Kim
- Department of Pharmacology, School of Dentistry, Kyungpook National University, Daegu 41940, Republic of Korea
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Li Z, Zhao Y, Suguro S, Suguro R. MicroRNAs Regulate Function in Atherosclerosis and Clinical Implications. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2023; 2023:2561509. [PMID: 37675243 PMCID: PMC10480027 DOI: 10.1155/2023/2561509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 07/05/2023] [Accepted: 08/10/2023] [Indexed: 09/08/2023]
Abstract
Background Atherosclerosis is considered the most common cause of morbidity and mortality worldwide. Athermanous plaque formation is pathognomonic of atherosclerosis. The main feature of atherosclerosis is the formation of plaque, which is inseparable from endothelial cells, vascular smooth muscle cells, and macrophages. MicroRNAs, a small highly conserved noncoding ribonucleic acid (RNA) molecule, have multiple biological functions, such as regulating gene transcription, silencing target gene expression, and affecting protein translation. MicroRNAs also have various pharmacological activities, such as regulating cell proliferation, apoptosis, and metabolic processes. It is noteworthy that many studies in recent years have also proved that microRNAs play a role in atherosclerosis. Methods To summarize the functions of microRNAs in atherosclerosis, we reviewed all relevant articles published in the PubMed database before June 2022, with keywords "atherosclerosis," "microRNA," "endothelial cells," "vascular smooth muscle cells," "macrophages," and "cholesterol homeostasis," briefly summarized a series of research progress on the function of microRNAs in endothelial cells, vascular smooth muscle cells, and macrophages and atherosclerosis. Results and Conclusion. In general, the expression levels of some microRNAs changed significantly in different stages of atherosclerosis pathogenesis; therefore, MicroRNAs may become new diagnostic biomarkers for atherosclerosis. In addition, microRNAs are also involved in the regulation of core processes such as endothelial dysfunction, plaque formation and stabilization, and cholesterol metabolism, which also suggests the great potential of microRNAs as a therapeutic target.
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Affiliation(s)
- Zhaoyi Li
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau SAR, China
| | - Yidan Zhao
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau SAR, China
| | - Sei Suguro
- Faculty of Medicine, School of Pharmacy, The Chinese University of Hong Kong, Shatin New Territories, Hong Kong SAR, China
| | - Rinkiko Suguro
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau SAR, China
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20
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Ekedi AVNB, Rozhkov AN, Shchekochikhin DY, Novikova NA, Kopylov PY, Bestavashvili AA, Ivanova TV, Zhelankin AV, Generozov EV, Konanov DN, Akselrod AS. Evaluation of microRNA Expression Features in Patients with Various Types of Arterial Damage: Thoracic Aortic Aneurysm and Coronary Atherosclerosis. J Pers Med 2023; 13:1161. [PMID: 37511774 PMCID: PMC10381304 DOI: 10.3390/jpm13071161] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 07/16/2023] [Accepted: 07/18/2023] [Indexed: 07/30/2023] Open
Abstract
Circulating serum miRNA are increasingly used as biomarkers and potential treatment targets in several clinical scenarios, including cardiovascular diseases. However, the current data on circulating miRNA in thoracic aorta aneurism (TAA) patients are inconclusive. The aim of the present study is to compare the levels of several circulating miRNA in patients with degenerative TAA, coronary artery disease (CAD), and controls for special profile identification. We have identified several candidates for the role of new biomarkers: miR-143-3p, miR-181-5p, miR-126-3p, miR-126-5p, miR-145-5p, miR-150-5p, and miR-195-5p. MATERIALS AND METHODS Serum samples of 100 patients were analyzed, including 388 TAA patients scheduled for elective surgery, 67 patients with stable CAD and 17 controls, were used for miRNA isolation and identification. RESULTS More specific for TAA with very high predictive ability in ROC analysis was an increase in the levels of miR-21-5p, miR-29b-5p, miR-126-5p/-3p, miR-181b-5p, and miR-92a-3p, with the latter microRNA being investigated as a novel potential marker of TAA for the first time. CONCLUSION TAA and CAD patients demonstrated a significant increase in the levels of circulating miR-126-5p/-3p, miR-181b-5p, and miR-29b-3p. More specific for TAA with very high predictive ability in ROC analysis was an increase in the levels of miR-21-5p, -29b-5p, -126-5p/-3p, 181b-5p, and -92a-3p, with the latter microRNA being investigated as a potential marker of TAA for the first time.
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Affiliation(s)
- Ange Veroniqe Ngo Bilong Ekedi
- Department of Cardiology, Functional and Ultrasound Diagnostics, N.V. Sklifosovsky Institute of Clinical Medicine, I. M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia
| | - Andrey N Rozhkov
- World-Class Research Center "Digital Biodesign and Personalized Healthcare", I. M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia
| | - Dmitry Yu Shchekochikhin
- Department of Cardiology, Functional and Ultrasound Diagnostics, N.V. Sklifosovsky Institute of Clinical Medicine, I. M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia
| | - Nina A Novikova
- Department of Cardiology, Functional and Ultrasound Diagnostics, N.V. Sklifosovsky Institute of Clinical Medicine, I. M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia
| | - Philippe Yu Kopylov
- Department of Cardiology, Functional and Ultrasound Diagnostics, N.V. Sklifosovsky Institute of Clinical Medicine, I. M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia
- World-Class Research Center "Digital Biodesign and Personalized Healthcare", I. M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia
| | - Afina A Bestavashvili
- World-Class Research Center "Digital Biodesign and Personalized Healthcare", I. M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia
| | - Tatiana V Ivanova
- Department of Cardiology, Functional and Ultrasound Diagnostics, N.V. Sklifosovsky Institute of Clinical Medicine, I. M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia
| | - Andrey V Zhelankin
- Federal Research and Clinical Center of Physical-Chemical Medicine, Federal Medical Biological Agency, 119435 Moscow, Russia
| | - Eduard V Generozov
- Federal Research and Clinical Center of Physical-Chemical Medicine, Federal Medical Biological Agency, 119435 Moscow, Russia
| | - Dmitry N Konanov
- Federal Research and Clinical Center of Physical-Chemical Medicine, Federal Medical Biological Agency, 119435 Moscow, Russia
| | - Anna S Akselrod
- Department of Cardiology, Functional and Ultrasound Diagnostics, N.V. Sklifosovsky Institute of Clinical Medicine, I. M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia
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Zapata-Martínez L, Águila S, de los Reyes-García AM, Carrillo-Tornel S, Lozano ML, González-Conejero R, Martínez C. Inflammatory microRNAs in cardiovascular pathology: another brick in the wall. Front Immunol 2023; 14:1196104. [PMID: 37275892 PMCID: PMC10233054 DOI: 10.3389/fimmu.2023.1196104] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 05/08/2023] [Indexed: 06/07/2023] Open
Abstract
The regulatory role of microRNAs (miRNAs) is mainly mediated by their effect on protein expression and is recognized in a multitude of pathophysiological processes. In recent decades, accumulating evidence has interest in these factors as modulatory elements of cardiovascular pathophysiology. Furthermore, additional biological processes have been identified as new components of cardiovascular disease etiology. In particular, inflammation is now considered an important cardiovascular risk factor. Thus, in the present review, we will focus on the role of a subset of miRNAs called inflamma-miRs that may regulate inflammatory status in the development of cardiovascular pathology. According to published data, the most representative candidates that play functional roles in thromboinflammation are miR-21, miR-33, miR-34a, miR-146a, miR-155, and miR-223. We will describe the functions of these miRNAs in several cardiovascular pathologies in depth, with specific emphasis on the molecular mechanisms related to atherogenesis. We will also discuss the latest findings on the role of miRNAs as regulators of neutrophil extracellular traps and their impact on cardiovascular diseases. Overall, the data suggest that the use of miRNAs as therapeutic tools or biomarkers may improve the diagnosis or prognosis of adverse cardiovascular events in inflammatory diseases. Thus, targeting or increasing the levels of adequate inflamma-miRs at different stages of disease could help mitigate or avoid the development of cardiovascular morbidities.
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22
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Fan T, Guo K, Cao F, Deng Z, Liu B, Shi M, Liu Y, Ma Z. Study on the effect of periodontitis on renal tissue in atherosclerotic mice. J Periodontal Res 2023; 58:655-667. [PMID: 37051685 DOI: 10.1111/jre.13128] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 03/19/2023] [Accepted: 03/30/2023] [Indexed: 04/14/2023]
Abstract
BACKGROUND AND OBJECTIVE Periodontitis is immune inflammatory disease, atherosclerosis (AS) and chronic kidney disease (CKD) are two common systemic diseases. Periodontitis promotes AS and CKD, and CKD interacts with AS. The objective of this animal study was to evaluate the changes of kidney when periodontitis and atherosclerosis exist separately and the degenerative effects of periodontitis on the kidney in atherosclerotic mice. MATERIALS AND METHODS A total of 40 male Apoe-/- mice were randomly divided into four groups: control (NC), periodontitis (PD), AS and AS with PD (AS + PD). AS was induced by high-fat diet feeding, and PD was induced by injection of Porphyromonas gingivalis-Lipopolysaccharide (P.g-LPS) (endotoxin suspension) into the buccal side of mouse maxillary molars. The right maxilla of mice was scanned with micro-CT to evaluate alveolar bone loss; aortic tissue was stained with HE and Oil-Red O to evaluate arterial plaque formation; serum was collected to detect the changes of blood lipids and serum renal function parameters (blood urea nitrogen [BUN], serum creatinine [Scr]); renal histopathological changes were evaluated by HE staining (glomerular and tubular damage scores), PAS staining (glomerular Mesangial matrix index) and Masson staining (percentage of renal fibrosis area); qRT-PCR and ELISA were used to evaluate the expression of renal inflammatory cytokines (tumor necrosis factor-α, Interleukin-1β, neutrophil surface marker Ly6G). RESULTS The amount of alveolar bone loss: PD group was significantly higher than NC group (p < .05); AS + PD group was higher than PD group, the difference was not statistically significant. Atherosclerotic plaque formation and serum lipid changes: AS group were significantly worse than NC group (p < .05), and AS + PD group were worse than AS group. The results of the corresponding qualitative and quantitative analyses of kidney tissue in experimental animals gradually deteriorated in the NC group, PD group, AS group and AS + PD group and worsened sequentially. Renal function parameters: the content of BUN in AS group was higher than that in PD group, the difference was not statistically significant; Scr in AS group was significantly higher than that in PD group (p < .05); the contents of BUN and Scr in AS + PD group were higher than those in AS group, the difference was not statistically significant. Glomerular and tubular damage scores: AS group were higher than PD group, the difference was not statistically significant; AS + PD group were significantly higher than AS group (p < .001). The ratio of glomerular mesangial matrix to glomerular area and the percentage of renal fibrosis area: AS group were significantly higher than PD group (p < .001), and AS + PD group were significantly higher than AS group (p < .001). Expression of inflammatory cytokines: AS group was higher than PD group, the difference was not statistically significant; AS + PD group was significantly higher than AS group (p < .05). CONCLUSION Both PD and AS can aggravate the inflammatory stress of kidney tissue and cause the damage of kidney tissue, and the inflammatory increase and damage effect of AS is stronger; PD can promote kidney damage of atherosclerotic mice by aggravating the renal inflammation in atherosclerotic mice; renal function parameters were not completely synchronized with the changes of renal inflammation and histopathology in each group of mice; PD can promote AS, periodontal inflammation in mice with AS is more severe, and the special changes of blood lipids in mice with AS are closely related to the above results.
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Affiliation(s)
- Tiantian Fan
- Department of Preventive Dentistry, Hebei Key Laboratory of Stomatology, Hebei Clinical Research Center for Oral Diseases, School and Hospital of Stomatology, Hebei Medical University, Shijiazhuang, China
| | - Kaili Guo
- Department of Preventive Dentistry, Hebei Key Laboratory of Stomatology, Hebei Clinical Research Center for Oral Diseases, School and Hospital of Stomatology, Hebei Medical University, Shijiazhuang, China
| | - Fengdi Cao
- Department of Preventive Dentistry, Hebei Key Laboratory of Stomatology, Hebei Clinical Research Center for Oral Diseases, School and Hospital of Stomatology, Hebei Medical University, Shijiazhuang, China
| | - Zhuohang Deng
- Department of Preventive Dentistry, Hebei Key Laboratory of Stomatology, Hebei Clinical Research Center for Oral Diseases, School and Hospital of Stomatology, Hebei Medical University, Shijiazhuang, China
| | - Bin Liu
- Department of Preventive Dentistry, Hebei Key Laboratory of Stomatology, Hebei Clinical Research Center for Oral Diseases, School and Hospital of Stomatology, Hebei Medical University, Shijiazhuang, China
| | - Mingyue Shi
- Department of Preventive Dentistry, Hebei Key Laboratory of Stomatology, Hebei Clinical Research Center for Oral Diseases, School and Hospital of Stomatology, Hebei Medical University, Shijiazhuang, China
| | - Yue Liu
- Department of Preventive Dentistry, Hebei Key Laboratory of Stomatology, Hebei Clinical Research Center for Oral Diseases, School and Hospital of Stomatology, Hebei Medical University, Shijiazhuang, China
| | - Zhe Ma
- Department of Preventive Dentistry, Hebei Key Laboratory of Stomatology, Hebei Clinical Research Center for Oral Diseases, School and Hospital of Stomatology, Hebei Medical University, Shijiazhuang, China
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Holland A, Enrick M, Diaz A, Yin L. Is miR-21 A Therapeutic Target in Cardiovascular Disease? INTERNATIONAL JOURNAL OF DRUG DISCOVERY AND PHARMACOLOGY 2023; 2:26-36. [PMID: 37799562 PMCID: PMC10552863 DOI: 10.53941/ijddp.0201003] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/07/2023]
Abstract
microRNA-21 (miR-21) serves a multitude of functions at the molecular level through its regulation of messenger RNA. Previous research has sparked interest in the role of miR-21 as a potential therapeutic target in cardiovascular diseases. miR-21 expression contributes to the differentiation, proliferation, and maturation of many cell types, such as fibroblasts, endothelial cells, cardiomyocytes, and endothelial progenitor cells. The function of miR-21 depends upon its expression level in the specific cell types and downstream targets, which determine cell fate. Under pathological conditions, the expression level of miR-21 is altered, leading to abnormal gene regulation of downstream signaling and cardiovascular diseases such as hypertension, cardiac hypertrophy and fibrosis, atherosclerosis, and heart failure. Agomirs or antagomirs can be introduced into the respective tissue type to reverse or stop the progression of the disease. Exosomes in the extracellular vesicles, which mediate many cellular events with high biocompatibility, have a high potential of efficiently delivering miR-21 to their targeted cells. The critical role of miR-21 in cardiovascular disease (CVD) is indisputable, but there are controversial reports on the function of miR-21 in the same disease. This discrepancy sparks interest in better understanding the role of miR-21 in different tissues under different stages of various diseases and the mechanism of how miR-21 inhibitors work.
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Affiliation(s)
- Antoinette Holland
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Ohio 44272, USA
| | - Molly Enrick
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Ohio 44272, USA
| | - Arianna Diaz
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Ohio 44272, USA
| | - Liya Yin
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Ohio 44272, USA
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Zhang Q, Wen XH, Tang SL, Zhao ZW, Tang CK. Role and therapeutic potential of gelsolin in atherosclerosis. J Mol Cell Cardiol 2023; 178:59-67. [PMID: 36967105 DOI: 10.1016/j.yjmcc.2023.03.012] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 03/16/2023] [Accepted: 03/21/2023] [Indexed: 04/08/2023]
Abstract
Atherosclerosis is the major pathophysiological basis of a variety of cardiovascular diseases and has been recognized as a lipid-driven chronic inflammatory disease. Gelsolin (GSN) is a member of the GSN family. The main function of GSN is to cut and seal actin filaments to regulate the cytoskeleton and participate in a variety of biological functions, such as cell movement, morphological changes, metabolism, apoptosis and phagocytosis. Recently, more and more evidences have demonstrated that GSN is Closely related to atherosclerosis, involving lipid metabolism, inflammation, cell proliferation, migration and thrombosis. This article reviews the role of GSN in atherosclerosis from inflammation, apoptosis, angiogenesis and thrombosis.
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Affiliation(s)
- Qiang Zhang
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, Department of Intensive Care Unit, the First Affiliated Hospital of University of South China, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Xiao-Hui Wen
- School of Nursing, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Shi-Lin Tang
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, Department of Intensive Care Unit, the First Affiliated Hospital of University of South China, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Zhen-Wang Zhao
- School of Basic Medicine, Hubei University of Arts and Science, Xiangyang, Hubei 441053, China.
| | - Chao-Ke Tang
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, Department of Intensive Care Unit, the First Affiliated Hospital of University of South China, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China.
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25
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The Role of ncRNAs in Cardiac Infarction and Regeneration. J Cardiovasc Dev Dis 2023; 10:jcdd10030123. [PMID: 36975887 PMCID: PMC10052289 DOI: 10.3390/jcdd10030123] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 03/06/2023] [Accepted: 03/13/2023] [Indexed: 03/17/2023] Open
Abstract
Myocardial infarction is the most prevalent cardiovascular disease worldwide, and it is defined as cardiomyocyte cell death due to a lack of oxygen supply. Such a temporary absence of oxygen supply, or ischemia, leads to extensive cardiomyocyte cell death in the affected myocardium. Notably, reactive oxygen species are generated during the reperfusion process, driving a novel wave of cell death. Consequently, the inflammatory process starts, followed by fibrotic scar formation. Limiting inflammation and resolving the fibrotic scar are essential biological processes with respect to providing a favorable environment for cardiac regeneration that is only achieved in a limited number of species. Distinct inductive signals and transcriptional regulatory factors are key components that modulate cardiac injury and regeneration. Over the last decade, the impact of non-coding RNAs has begun to be addressed in many cellular and pathological processes including myocardial infarction and regeneration. Herein, we provide a state-of-the-art review of the current functional role of diverse non-coding RNAs, particularly microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), in different biological processes involved in cardiac injury as well as in distinct experimental models of cardiac regeneration.
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Sprenkle NT, Serezani CH, Pua HH. MicroRNAs in Macrophages: Regulators of Activation and Function. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2023; 210:359-368. [PMID: 36724439 PMCID: PMC10316964 DOI: 10.4049/jimmunol.2200467] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 10/13/2022] [Indexed: 02/03/2023]
Abstract
Macrophages are sentinels of the innate immune system that maintain tissue homeostasis and contribute to inflammatory responses. Their broad scope of action depends on both functional heterogeneity and plasticity. Small noncoding RNAs called microRNAs (miRNAs) contribute to macrophage function as post-transcriptional inhibitors of target gene networks. Genetic and pharmacologic studies have uncovered genes regulated by miRNAs that control macrophage cellular programming and macrophage-driven pathology. miRNAs control proinflammatory M1-like activation, immunoregulatory M2-like macrophage activation, and emerging macrophage functions in metabolic disease and innate immune memory. Understanding the gene networks regulated by individual miRNAs enhances our understanding of the spectrum of macrophage function at steady state and during responses to injury or pathogen invasion, with the potential to develop miRNA-based therapies. This review aims to consolidate past and current studies investigating the complexity of the miRNA interactome to provide the reader with a mechanistic view of how miRNAs shape macrophage behavior.
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Affiliation(s)
| | - C Henrique Serezani
- Department of Pathology, Microbiology, and Immunology
- Department of Medicine, Division of Infectious Diseases
- Vanderbilt Center for Immunobiology, Nashville, Tennessee 37232, USA
- Vandebilt Institute of Infection, Immunology and Inflammation; Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
| | - Heather H Pua
- Department of Pathology, Microbiology, and Immunology
- Vanderbilt Center for Immunobiology, Nashville, Tennessee 37232, USA
- Vandebilt Institute of Infection, Immunology and Inflammation; Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
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Hong Y, Zhang Y, Chen H, Tang X, Zhao H, Meng Z, Jia X, Liu W, Li X, Wang L, Zhong X, Bai X, Sun H, Kopylov P, Afina B, Shchekochikhin D, Zhang Y, Liu X, Fan Y. Genetic dissection of the impact of lncRNA AI662270 during the development of atherosclerosis. J Transl Med 2023; 21:97. [PMID: 36755320 PMCID: PMC9906833 DOI: 10.1186/s12967-023-03962-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 02/02/2023] [Indexed: 02/10/2023] Open
Abstract
BACKGROUND Atherosclerosis is driven by synergistic interactions between pathological biomechanical and lipid metabolic factors. Long noncoding RNAs (LncRNAs) have been implicated in atherogenesis. The purpose of this study was to investigate the potential mechanism of lncRNA AI662270 on macrophage cholesterol transport in atherosclerosis. METHODS Apolipoprotein E deficiency (ApoE-/-) mice were fed a high fat diet for 16 weeks to construct atherosclerotic model, and the mice were injected with recombinant lentivirus carrying AI662270 gene to overexpress AI662270. Macrophages were cleared by liposomal clondronate in vivo. Fundamental experiments and functional assays, hematoxylin and eosin staining, oil red O staining and others, were performed to evaluate the function of AI662270 on atherogenesis. Peritoneal macrophages were treated with oxidized low density lipoprotein (ox-LDL) to simulate in vitro model. Mechanism assays, RNA-interacting protein immunoprecipitation, RNA-protein pulldown and others, were performed to study the regulatory mechanism of AI662270 in macrophages. RESULTS The novel AI662270 was mainly enriched in macrophages, but not in endothelial cells, smooth muscle cells and fibroblasts of mouse atherosclerotic lesions and was upregulated by ox-LDL. Overexpression of AI662270 resulted in lipid accumulation, larger atherosclerotic plaques and cardiac dysfunction in vivo. After macrophages were removed, the pro-atherogenic effect of AI662270 disappeared. Downregulation of AI662270 in macrophages protected against foam cell formation by potentiating cholesterol efflux and reducing intracellular total cholesterol. The opposite effect was observed in macrophage-specific AI662270-overexpressed cells in vitro. AI662270 bound to adenosine triphosphate-binding cassette transporter A1 (Abca1) responsible for regulating cholesterol efflux in macrophages. Forced expression of AI662270 in macrophages decreased Abca1 expression. The reverse occurred when expression of AI662270 was repressed. CONCLUSION These findings reveal an essential role for AI662270 in atherosclerosis progression by regulating cholesterol efflux from macrophages.
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Affiliation(s)
- Yang Hong
- grid.410736.70000 0001 2204 9268Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin, 150081 Heilongjiang People’s Republic of China
| | - Yue Zhang
- grid.410736.70000 0001 2204 9268Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin, 150081 Heilongjiang People’s Republic of China
| | - Hui Chen
- grid.410736.70000 0001 2204 9268Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin, 150081 Heilongjiang People’s Republic of China
| | - Xueqing Tang
- grid.410736.70000 0001 2204 9268Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin, 150081 Heilongjiang People’s Republic of China
| | - Hongrui Zhao
- grid.410736.70000 0001 2204 9268Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin, 150081 Heilongjiang People’s Republic of China
| | - Ziyu Meng
- grid.410736.70000 0001 2204 9268Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin, 150081 Heilongjiang People’s Republic of China
| | - Xueling Jia
- grid.410736.70000 0001 2204 9268Department of Pathology and Pathophysiology, College of Basic Medical Sciences, Harbin Medical University-Daqing, Daqing, 163319 Heilongjiang People’s Republic of China
| | - Wenfeng Liu
- grid.410736.70000 0001 2204 9268Department of Pathology and Pathophysiology, College of Basic Medical Sciences, Harbin Medical University-Daqing, Daqing, 163319 Heilongjiang People’s Republic of China
| | - Xiaohan Li
- grid.410736.70000 0001 2204 9268Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin, 150081 Heilongjiang People’s Republic of China
| | - Lin Wang
- grid.410736.70000 0001 2204 9268Department of Pathology and Pathophysiology, College of Basic Medical Sciences, Harbin Medical University-Daqing, Daqing, 163319 Heilongjiang People’s Republic of China
| | - Xinrui Zhong
- grid.410736.70000 0001 2204 9268Department of Pathology and Pathophysiology, College of Basic Medical Sciences, Harbin Medical University-Daqing, Daqing, 163319 Heilongjiang People’s Republic of China
| | - Xuefeng Bai
- grid.410736.70000 0001 2204 9268School of Medical Informatics, Harbin Medical University, Daqing Campus, Daqing, 163319 People’s Republic of China
| | - Heyang Sun
- grid.410736.70000 0001 2204 9268Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin, 150081 Heilongjiang People’s Republic of China
| | - Philipp Kopylov
- grid.410736.70000 0001 2204 9268Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin, 150081 Heilongjiang People’s Republic of China ,grid.448878.f0000 0001 2288 8774Department of Preventive and Emergency Cardiology, Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | - Bestavashvili Afina
- grid.410736.70000 0001 2204 9268Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin, 150081 Heilongjiang People’s Republic of China ,grid.448878.f0000 0001 2288 8774Department of Cardiology, Functional and Ultrasound Diagnostics, N.V. Sklifosofsky, I. M. Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | - Dmitry Shchekochikhin
- grid.410736.70000 0001 2204 9268Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin, 150081 Heilongjiang People’s Republic of China ,grid.448878.f0000 0001 2288 8774Department of Preventive and Emergency Cardiology, Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | - Yong Zhang
- grid.410736.70000 0001 2204 9268Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin, 150081 Heilongjiang People’s Republic of China
| | - Xin Liu
- Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin, 150081, Heilongjiang, People's Republic of China.
| | - Yuhua Fan
- Department of Pathology and Pathophysiology, College of Basic Medical Sciences, Harbin Medical University-Daqing, Daqing, 163319, Heilongjiang, People's Republic of China. .,Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin, 150081, Heilongjiang, People's Republic of China.
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Ding J, Wu L, Zhu G, Zhu J, Luo P, Li Y. HADHA alleviates hepatic steatosis and oxidative stress in NAFLD via inactivation of the MKK3/MAPK pathway. Mol Biol Rep 2023; 50:961-970. [PMID: 36376538 PMCID: PMC9889437 DOI: 10.1007/s11033-022-07965-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 09/22/2022] [Indexed: 11/16/2022]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is a liver metabolic syndrome and still lacks effective treatments because the molecular mechanism underlying the development of NAFLD is not completely understood. We investigated the role of Hydroxyl CoA dehydrogenase alpha subunit (HADHA) in the pathogenesis of NAFLD. METHODS HADHA expression was detected both in NAFLD cell and mice, and knockdown of HADHA in free fatty acids (FFA)-treated L02 or overexpression of HADHA in high fat diet (HFD)-fed mice was used to detected the influence of HADHA on hepatic steatosis, mitochondrial dysfunction, and oxidative stress by regulating of MKK3/MAPK signaling. RESULTS Our data revealed that HADHA expression was decreased in FFA-treated L02 cells and in HFD-fed mice. Knockdown of HADHA markedly aggravated hepatic steatosis, inflammation and oxidative stress in FFA-treated L02 cells, which was associated with the activation of MKK3/MAPK signalling pathways. Moreover, oxidative stress and liver lesions were improved in NAFLD mice by upregulation of HADHA. Importantly, we demonstrated that overexpression of HADHA inhibited the expression of p-MAPK in NAFLD mice, reducing lipid accumulation and steatosis. CONCLUSION HADHA may function as a protective factor in the progression of NAFLD by alleviating abnormal metabolism and oxidative stress by suppressing MKK3/MAPK signalling pathway activation, providing a new target for the treatment of NAFLD.
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Affiliation(s)
- Jiexia Ding
- Department of Infectious Diseases, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, No. 261 Huansha Road, 310003, Hangzhou, Zhejiang Province, China.
| | - Lili Wu
- Department of Oncology, Ruian City People's Hospital, 325200, Rui'an, China
| | - Guoxian Zhu
- Department of Infectious Diseases, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, No. 261 Huansha Road, 310003, Hangzhou, Zhejiang Province, China
| | - Jing Zhu
- Department of Infectious Diseases, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, No. 261 Huansha Road, 310003, Hangzhou, Zhejiang Province, China
| | - Pingping Luo
- Department of Infectious Diseases, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, No. 261 Huansha Road, 310003, Hangzhou, Zhejiang Province, China
| | - Youming Li
- Department of Gastroenterology, Zhejiang University School of Medicine First Affiliated Hospital, 310003, Hangzhou, China
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Impact of air pollution on ischemic heart disease: Evidence, mechanisms, clinical perspectives. Atherosclerosis 2023; 366:22-31. [PMID: 36696748 DOI: 10.1016/j.atherosclerosis.2023.01.013] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 12/23/2022] [Accepted: 01/17/2023] [Indexed: 01/22/2023]
Abstract
Ambient air pollution, and especially particulate matter (PM) air pollution <2.5 μm in diameter (PM2.5), has clearly emerged as an important yet often overlooked risk factor for atherosclerosis and ischemic heart disease (IHD). In this review, we examine the available evidence demonstrating how acute and chronic PM2.5 exposure clinically translates into a heightened coronary atherosclerotic burden and an increased risk of acute ischemic coronary events. Moreover, we provide insights into the pathophysiologic mechanisms underlying PM2.5-mediated atherosclerosis, focusing on the specific biological mechanism through which PM2.5 exerts its detrimental effects. Further, we discuss about the possible mechanisms that explain the recent findings reporting a strong association between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, increased PM2.5 exposure, and morbidity and mortality from IHD. We also address the possible mitigation strategies that should be implemented to reduce the impact of PM2.5 on cardiovascular morbidity and mortality, and underscoring the strong need of clinical trials demonstrating the efficacy of specific interventions (including both PM2.5 reduction and/or specific drugs) in reducing the incidence of IHD. Finally, we introduce the emerging concept of the exposome, highlighting the close relationship between PM2.5 and other environmental exposures (i.e.: traffic noise and climate change) in terms of common underlying pathophysiologic mechanisms and possible mitigation strategies.
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Canfrán-Duque A, Rotllan N, Zhang X, Andrés-Blasco I, Thompson BM, Sun J, Price NL, Fernández-Fuertes M, Fowler JW, Gómez-Coronado D, Sessa WC, Giannarelli C, Schneider RJ, Tellides G, McDonald JG, Fernández-Hernando C, Suárez Y. Macrophage-Derived 25-Hydroxycholesterol Promotes Vascular Inflammation, Atherogenesis, and Lesion Remodeling. Circulation 2023; 147:388-408. [PMID: 36416142 PMCID: PMC9892282 DOI: 10.1161/circulationaha.122.059062] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 10/20/2022] [Indexed: 11/24/2022]
Abstract
BACKGROUND Cross-talk between sterol metabolism and inflammatory pathways has been demonstrated to significantly affect the development of atherosclerosis. Cholesterol biosynthetic intermediates and derivatives are increasingly recognized as key immune regulators of macrophages in response to innate immune activation and lipid overloading. 25-Hydroxycholesterol (25-HC) is produced as an oxidation product of cholesterol by the enzyme cholesterol 25-hydroxylase (CH25H) and belongs to a family of bioactive cholesterol derivatives produced by cells in response to fluctuating cholesterol levels and immune activation. Despite the major role of 25-HC as a mediator of innate and adaptive immune responses, its contribution during the progression of atherosclerosis remains unclear. METHODS The levels of 25-HC were analyzed by liquid chromatography-mass spectrometry, and the expression of CH25H in different macrophage populations of human or mouse atherosclerotic plaques, respectively. The effect of CH25H on atherosclerosis progression was analyzed by bone marrow adoptive transfer of cells from wild-type or Ch25h-/- mice to lethally irradiated Ldlr-/- mice, followed by a Western diet feeding for 12 weeks. Lipidomic, transcriptomic analysis and effects on macrophage function and signaling were analyzed in vitro from lipid-loaded macrophage isolated from Ldlr-/- or Ch25h-/-;Ldlr-/- mice. The contribution of secreted 25-HC to fibrous cap formation was analyzed using a smooth muscle cell lineage-tracing mouse model, Myh11ERT2CREmT/mG;Ldlr-/-, adoptively transferred with wild-type or Ch25h-/- mice bone marrow followed by 12 weeks of Western diet feeding. RESULTS We found that 25-HC accumulated in human coronary atherosclerotic lesions and that macrophage-derived 25-HC accelerated atherosclerosis progression, promoting plaque instability through autocrine and paracrine actions. 25-HC amplified the inflammatory response of lipid-loaded macrophages and inhibited the migration of smooth muscle cells within the plaque. 25-HC intensified inflammatory responses of lipid-laden macrophages by modifying the pool of accessible cholesterol in the plasma membrane, which altered Toll-like receptor 4 signaling, promoted nuclear factor-κB-mediated proinflammatory gene expression, and increased apoptosis susceptibility. These effects were independent of 25-HC-mediated modulation of liver X receptor or SREBP (sterol regulatory element-binding protein) transcriptional activity. CONCLUSIONS Production of 25-HC by activated macrophages amplifies their inflammatory phenotype, thus promoting atherogenesis.
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Affiliation(s)
- Alberto Canfrán-Duque
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut, USA
- Yale Center for Molecular and System Metabolism, Yale University School of Medicine, New Haven, Connecticut, USA
- Department of Comparative Medicine. Yale University School of Medicine, New Haven, Connecticut, USA
| | - Noemi Rotllan
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut, USA
- Yale Center for Molecular and System Metabolism, Yale University School of Medicine, New Haven, Connecticut, USA
- Department of Comparative Medicine. Yale University School of Medicine, New Haven, Connecticut, USA
| | - Xinbo Zhang
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut, USA
- Yale Center for Molecular and System Metabolism, Yale University School of Medicine, New Haven, Connecticut, USA
- Department of Comparative Medicine. Yale University School of Medicine, New Haven, Connecticut, USA
| | - Irene Andrés-Blasco
- Department of Comparative Medicine. Yale University School of Medicine, New Haven, Connecticut, USA
- Genomics and Diabetes Unit, Health Research Institute Clinic Hospital of Valencia (INCLIVA), Valencia, Spain
| | - Bonne M Thompson
- Center for Human Nutrition. University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Jonathan Sun
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut, USA
- Yale Center for Molecular and System Metabolism, Yale University School of Medicine, New Haven, Connecticut, USA
- Department of Pathology. Yale University School of Medicine, New Haven, Connecticut, USA
| | - Nathan L Price
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut, USA
- Yale Center for Molecular and System Metabolism, Yale University School of Medicine, New Haven, Connecticut, USA
- Department of Comparative Medicine. Yale University School of Medicine, New Haven, Connecticut, USA
| | - Marta Fernández-Fuertes
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut, USA
- Yale Center for Molecular and System Metabolism, Yale University School of Medicine, New Haven, Connecticut, USA
- Department of Comparative Medicine. Yale University School of Medicine, New Haven, Connecticut, USA
| | - Joseph W. Fowler
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut, USA
- Department of Pharmacology Yale University School of Medicine, New Haven, Connecticut, USA
| | - Diego Gómez-Coronado
- Servicio Bioquímica-Investigación, Hospital Universitario Ramón y Cajal, IRyCIS, Madrid, and CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Spain
| | - William C. Sessa
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut, USA
- Department of Pharmacology Yale University School of Medicine, New Haven, Connecticut, USA
| | - Chiara Giannarelli
- Department of Medicine, Cardiology, NYU Grossman School of Medicine, New York, New York, USA
- Department of Pathology, NYU Grossman School of Medicine, New York, New York, USA
| | - Robert J Schneider
- Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA
| | - George Tellides
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut, USA
- Department of Surgery, Yale University School of Medicine, New Haven, Connecticut, 06520 USA
| | - Jeffrey G McDonald
- Center for Human Nutrition. University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Carlos Fernández-Hernando
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut, USA
- Yale Center for Molecular and System Metabolism, Yale University School of Medicine, New Haven, Connecticut, USA
- Department of Comparative Medicine. Yale University School of Medicine, New Haven, Connecticut, USA
- Department of Pathology. Yale University School of Medicine, New Haven, Connecticut, USA
| | - Yajaira Suárez
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut, USA
- Yale Center for Molecular and System Metabolism, Yale University School of Medicine, New Haven, Connecticut, USA
- Department of Comparative Medicine. Yale University School of Medicine, New Haven, Connecticut, USA
- Department of Pathology. Yale University School of Medicine, New Haven, Connecticut, USA
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Teixeira AR, Ferreira VV, Pereira-da-Silva T, Ferreira RC. The role of miRNAs in the diagnosis of stable atherosclerosis of different arterial territories: A critical review. Front Cardiovasc Med 2022; 9:1040971. [PMID: 36505351 PMCID: PMC9733725 DOI: 10.3389/fcvm.2022.1040971] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Accepted: 10/20/2022] [Indexed: 11/26/2022] Open
Abstract
Atherosclerotic disease is a major cause of morbidity and mortality worldwide. Atherosclerosis may be present in different arterial territories and as a single- or multi-territorial disease. The different phenotypes of atherosclerosis are attributable only in part to acquired cardiovascular risk factors and genetic Mendelian inheritance. miRNAs, which regulate the gene expression at the post-transcriptional level, may also contribute to such heterogeneity. Numerous miRNAs participate in the pathophysiology of atherosclerosis by modulating endothelial function, smooth vascular cell function, vascular inflammation, and cholesterol homeostasis in the vessel, among other biological processes. Moreover, miRNAs are present in peripheral blood with high stability and have the potential to be used as non-invasive biomarkers for the diagnosis of atherosclerosis. However, the circulating miRNA profile may vary according to the involved arterial territory, considering that atherosclerosis expression, including the associated molecular phenotype, varies according to the affected arterial territory. In this review, we discuss the specific circulating miRNA profiles associated with atherosclerosis of different arterial territories, the common circulating miRNA profile of stable atherosclerosis irrespective of the involved arterial territory, and the circulating miRNA signature of multi-territorial atherosclerosis. miRNAs may consist of a simple non-invasive method for discriminating atherosclerosis of different arterial sites. The limitations of miRNA profiling for such clinical application are also discussed.
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Affiliation(s)
- Ana Rita Teixeira
- Department of Cardiology, Hospital de Santa Marta, Centro Hospitalar Universitário de Lisboa Central, Lisbon, Portugal
- *Correspondence: Ana Rita Teixeira
| | - Vera Vaz Ferreira
- Department of Cardiology, Hospital de Santa Marta, Centro Hospitalar Universitário de Lisboa Central, Lisbon, Portugal
| | - Tiago Pereira-da-Silva
- Department of Cardiology, Hospital de Santa Marta, Centro Hospitalar Universitário de Lisboa Central, Lisbon, Portugal
- NOVA Medical School | Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisbon, Portugal
| | - Rui Cruz Ferreira
- Department of Cardiology, Hospital de Santa Marta, Centro Hospitalar Universitário de Lisboa Central, Lisbon, Portugal
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Kabłak-Ziembicka A, Badacz R, Przewłocki T. Clinical Application of Serum microRNAs in Atherosclerotic Coronary Artery Disease. J Clin Med 2022; 11:6849. [PMID: 36431326 PMCID: PMC9698927 DOI: 10.3390/jcm11226849] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 11/15/2022] [Accepted: 11/18/2022] [Indexed: 11/22/2022] Open
Abstract
MicroRNAs (miRs) are promising diagnostic, prognostic and therapeutic biomolecules for atherosclerotic cardiovascular disease. Atherosclerotic occlusive disease concerns a large population of patients, carrying the highest incidence of fatal and non-fatal adverse events, such as myocardial infarction, ischemic stroke, and limb ischemia, worldwide. Consistently, miRs are involved in regulation and pathogenesis of atherosclerotic coronary artery disease (CAD), acute coronary syndromes (ACS), both with ST-segment (STEMI) and non-ST segment elevation myocardial infarctions (NSTEMI), as well as cardiac remodeling and fibrosis following ACS. However, the genetic and molecular mechanisms underlying adverse outcomes in CAD are multifactorial, and sometimes difficult to interpret for clinicians. Therefore, in the present review paper we have focused on the clinical meaning and the interpretation of various miRs findings, and their potential application in routine clinical practice.
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Affiliation(s)
- Anna Kabłak-Ziembicka
- Department of Interventional Cardiology, Institute of Cardiology, Jagiellonian University Medical College, św. Anny 12, 31-007 Kraków, Poland
- Noninvasive Cardiovascular Laboratory, The John Paul II Hospital, Prądnicka 80, 31-202 Kraków, Poland
| | - Rafał Badacz
- Department of Interventional Cardiology, Institute of Cardiology, Jagiellonian University Medical College, św. Anny 12, 31-007 Kraków, Poland
- Department of Interventional Cardiology, The John Paul II Hospital, Prądnicka 80, 31-202 Kraków, Poland
| | - Tadeusz Przewłocki
- Department of Interventional Cardiology, The John Paul II Hospital, Prądnicka 80, 31-202 Kraków, Poland
- Department of Cardiac and Vascular Diseases, Institute of Cardiology, Jagiellonian University Medical College, św. Anny 12, 31-007 Kraków, Poland
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Luo HY, Li G, Liu YG, Wei YH, Chen JB, Gu XF, Tang JQ, Zhao Y, Su CH, Xiao LY, Xiong F, Zheng ZD, Wang SY, Zha LY. The Accelerated Progression of Atherosclerosis Correlates with Decreased miR-33a and miR-21 and Increased miR-122 and miR-3064-5p in Circulation and the Liver of ApoE-/- Mice with Streptozocin (STZ)-Induced Type 2 Diabetes. Curr Issues Mol Biol 2022; 44:4822-4837. [PMID: 36286043 PMCID: PMC9601109 DOI: 10.3390/cimb44100328] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 10/09/2022] [Accepted: 10/11/2022] [Indexed: 11/16/2022] Open
Abstract
Atherosclerosis is a major risk factor for type 2 diabetes (T2D) mortality. We aim to investigate the changes in miR-21, miR-122, miR-33a and miR-3064-5p in circulation and the liver of ApoE-/- mice with streptozocin (STZ)-induced T2D. Twenty 5-week-old male ApoE-/- mice were randomly assigned to the control (n = 10) and T2D group (n = 10) and intraperitoneally injected with a citrate buffer and streptozotocin (STZ) (40 mg/kg BW) once a day for three consecutive days. The successfully STZ-induced T2D mice (n = 5) and control mice (n = 5) were then fed with a high-fat diet (HFD) for 34 weeks. Compared to the control mice, ApoE-/- mice with STZ-induced T2D had slower (p < 0.05) growth, increased (p < 0.05) total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), decreased (p < 0.05) high-density lipoprotein cholesterol (HDL-C) in serum, reduced (p < 0.05) TC and sterol regulatory element-binding protein-2 (Srebp-2), elevated (p < 0.05) ATP-binding-cassette-transporter-A1 (Abca1) in the liver, aggravated (p < 0.05) atherosclerotic lesions in the aorta, downregulated (p < 0.05) miR-21 and miR-33a, and upregulated (p < 0.05) miR-122 and miR-3064-5p in serum and the liver. In addition, the aortic lesions showed a positive correlation with miR-122 (r = 1.000, p = 0.001) and a negative correlation with miR-21 (r = −1.000, p = 0.001) in ApoE-/- mice with T2D. In conclusion, T2D-accelerated atherosclerosis correlates with a reduction in miR-21 and miR-33a and an elevation in miR-122 and miR-3064-5p in circulation and the liver of ApoE-/- mice.
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Lyu L, Cai Y, Zhang G, Jing Z, Liang J, Zhang R, Dang X, Zhang C. Exosomes derived from M2 macrophages induce angiogenesis to promote wound healing. Front Mol Biosci 2022; 9:1008802. [PMID: 36304927 PMCID: PMC9592913 DOI: 10.3389/fmolb.2022.1008802] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 09/26/2022] [Indexed: 11/24/2022] Open
Abstract
There is an urgent clinical need for an appropriate method to shorten skin healing time. Among most factors related to wound healing, M2 macrophages will be recruited to the wound area and play a pivotal role in a time-limiting factor, angiogenesis. The exploration of exosomes derived from M2 in angiogenesis promotion is an attractive research field. In this project, we found that exosomes from M2 (M2-EXO) promoted the angiogenic ability of HUVECs in vitro. With a series of characteristic experiments, we demonstrated that M2-EXO inhibited PTEN expression in HUVECs by transferring miR-21, and further activated AKT/mTOR pathway. Then, using a full-thickness cutaneous wound mice model, we demonstrated that M2-EXO could be used as a promotor of angiogenesis and regeneration in vivo. Furthermore, M2-EXO-treated skin wounds exhibited regeneration of functional microstructures. These results demonstrate that M2-EXO can be used as a promising nanomedicine strategy for therapeutic exploration of skin healing with the potential to be translated into clinical practice.
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Affiliation(s)
| | | | | | | | | | | | - Xiaoqian Dang
- Department of Orthopedics, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Chen Zhang
- Department of Orthopedics, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
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Díez-Ricote L, Ruiz-Valderrey P, Micó V, Blanco R, Tomé-Carneiro J, Dávalos A, Ordovás JM, Daimiel L. TMAO Upregulates Members of the miR-17/92 Cluster and Impacts Targets Associated with Atherosclerosis. Int J Mol Sci 2022; 23:ijms232012107. [PMID: 36292963 PMCID: PMC9603323 DOI: 10.3390/ijms232012107] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 09/30/2022] [Accepted: 10/08/2022] [Indexed: 11/24/2022] Open
Abstract
Atherosclerosis is a hallmark of cardiovascular disease, and lifestyle strongly impacts its onset and progression. Nutrients have been shown to regulate the miR-17/92 cluster, with a role in endothelial function and atherosclerosis. Choline, betaine, and L-carnitine, found in animal foods, are metabolized into trimethylamine (TMA) by the gut microbiota. TMA is then oxidized to TMAO, which has been associated with atherosclerosis. Our aim was to investigate whether TMAO modulates the expression of the miR-17/92 cluster, along with the impact of this modulation on the expression of target genes related to atherosclerosis and inflammation. We treated HepG-2 cells, THP-1 cells, murine liver organoids, and human peripheral mononuclear cells with 6 µM of TMAO at different timepoints. TMAO increased the expression of all analyzed members of the cluster, except for miR-20a-5p in murine liver organoids and primary human macrophages. Genes and protein levels of SERPINE1 and IL-12A increased. Both have been associated with atherosclerosis and cardiovascular disease (CDVD) and are indirectly modulated by the miR-17-92 cluster. We concluded that TMAO modulates the expression of the miR-17/92 cluster and that such modulation could promote inflammation through IL-12A and blood clotting through SERPINE1 expression, which could ultimately promote atherosclerosis and CVD.
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Affiliation(s)
- Laura Díez-Ricote
- Nutritional Control of the Epigenome Group, Precision Nutrition and Obesity Program, IMDEA Food, UAM + CSIC, 28049 Madrid, Spain
| | - Paloma Ruiz-Valderrey
- Nutritional Control of the Epigenome Group, Precision Nutrition and Obesity Program, IMDEA Food, UAM + CSIC, 28049 Madrid, Spain
| | - Víctor Micó
- Nutritional Control of the Epigenome Group, Precision Nutrition and Obesity Program, IMDEA Food, UAM + CSIC, 28049 Madrid, Spain
| | - Ruth Blanco
- Nutritional Control of the Epigenome Group, Precision Nutrition and Obesity Program, IMDEA Food, UAM + CSIC, 28049 Madrid, Spain
- Research and Development Department, Biosearch Life Company, 28031 Madrid, Spain
| | - Joao Tomé-Carneiro
- Epigenetics of Lipid Metabolism Group, Precision Nutrition and Cardiometabolic Health Program, IMDEA Food, UAM + CSIC, 28049 Madrid, Spain
| | - Alberto Dávalos
- Epigenetics of Lipid Metabolism Group, Precision Nutrition and Cardiometabolic Health Program, IMDEA Food, UAM + CSIC, 28049 Madrid, Spain
| | - José M. Ordovás
- Nutritional Control of the Epigenome Group, Precision Nutrition and Obesity Program, IMDEA Food, UAM + CSIC, 28049 Madrid, Spain
- Nutrition and Genomics Laboratory, JM_USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111, USA
| | - Lidia Daimiel
- Nutritional Control of the Epigenome Group, Precision Nutrition and Obesity Program, IMDEA Food, UAM + CSIC, 28049 Madrid, Spain
- Correspondence: ; Tel.: +34-917278100 (ext. 309)
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36
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Suppression of Hepatic PPARα in Primary Biliary Cholangitis Is Modulated by miR-155. Cells 2022; 11:cells11182880. [PMID: 36139455 PMCID: PMC9496720 DOI: 10.3390/cells11182880] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 09/08/2022] [Accepted: 09/10/2022] [Indexed: 12/12/2022] Open
Abstract
Background: PPARα is a ligand-activated transcription factor that shows protective effects against metabolic disorders, inflammation and apoptosis. Primary biliary cholangitis and primary sclerosing cholangitis result in the intrahepatic accumulation of bile acids that leads to liver dysfunction and damage. Small, non-coding RNAs such as miR-155 and miR-21 are associated with silencing PPARα. Methods: The expression of miR-155, miR-21 and PPARα were evaluated using real-time PCR on liver tissue, as well as on human hepatocytes (HepG2) or cholangiocytes (NHCs) following exposure to lipopolysaccharide (LPS), glycodeoxycholic acid (GCDCA), lithocholic acid (LCA) and/or ursodeoxycholic acid (UDCA). Results: A reduction of PPARα in primary biliary cholangitis (PBC) livers was associated with miR-21 and miR-155 upregulation. Experimental overexpression of either miR-155 or miR-21 inhibited PPARα in hepatocytes, whereas, in cholangiocytes, only miR-21 suppressed PPARα. Both GCDCA and LCA induced the cell type-specific upregulation of miR-155 or miR-21. In HepG2, LPS-induced miR-155 expression was blocked by a cotreatment with UDCA and was associated with PPARα upregulation. In NHC cells, the expression of miR-21 was induced by LPS but did not affect PPARα expression. Conclusions: Hepatic PPARα expression is reduced in PBC livers as a likely result of miR-155 overexpression. UDCA effectively reduced both baseline and LPS-induced miR-155 expression, thus preventing the suppression of PPARα.
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Sajjadi E, Gaudioso G, Terrasi A, Boggio F, Venetis K, Ivanova M, Bertolasi L, Lopez G, Runza L, Premoli A, Lorenzini D, Guerini-Rocco E, Ferrero S, Vaira V, Fusco N. Osteoclast-like stromal giant cells in breast cancer likely belong to the spectrum of immunosuppressive tumor-associated macrophages. Front Mol Biosci 2022; 9:894247. [PMID: 36090031 PMCID: PMC9462457 DOI: 10.3389/fmolb.2022.894247] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 07/28/2022] [Indexed: 12/11/2022] Open
Abstract
Background: Breast cancer with osteoclast-like stromal giant cells (OSGC) is an exceedingly rare morphological pattern of invasive breast carcinoma. The tumor immune microenvironment (TIME) of these tumors is populated by OSGC, which resemble osteoclasts and show a histiocytic-like immunophenotype. Their role in breast cancer is unknown. The osteoclast maturation in the bone is regulated by the expression of cytokines that are also present in the TIME of tumors and in breast cancer tumor-associated macrophages (TAMs). TAMs-mediated anti-tumor immune pathways are regulated by miRNAs akin to osteoclast homeostasis. Here, we sought to characterize the different cellular compartments of breast cancers with OSGC and investigate the similarities of OSGC with tumor and TIME in terms of morphology, protein, and miRNA expression, specifically emphasizing on monocytic signatures. Methods and Results: Six breast cancers with OSGC were included. Tumor-infiltrating lymphocytes (TILs) and TAMs were separately quantified. The different cellular populations (i.e., normal epithelium, cancer cells, and OSGC) were isolated from tissue sections by laser-assisted microdissection. After RNA purification, 752 miRNAs were analyzed using a TaqMan Advanced miRNA Low-Density Array for all samples. Differentially expressed miRNAs were identified by computing the fold change (log2Ratio) using the Kolmogorov-Smirnov test and p values were corrected for multiple comparisons using the false discovery rate (FDR) approach. As a similarity analysis among samples, we used the Pearson test. The association between pairs of variables was investigated using Fisher exact test. Classical and non-classical monocyte miRNA signatures were finally applied. All OSGC displayed CD68 expression, TILs (range, 45–85%) and high TAMs (range, 35–75%). Regarding the global miRNAs profile, OSGC was more similar to cancer cells than to non-neoplastic ones. Shared deregulation of miR-143-3p, miR-195-5p, miR-181a-5p, and miR-181b-5p was observed between OSGC and cancer cells. The monocyte-associated miR-29a-3p and miR-21-3p were dysregulated in OSGCs compared with non-neoplastic or breast cancer tissues. Conclusion: Breast cancers with OSGC have an activated TIME. Shared epigenetic events occur during the ontogenesis of breast cancer cells and OSGC but the innumophenotype and miRNA profiles of the different cellular compartmens suggest that OSGC likely belong to the spectrum of M2 TAMs.
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Affiliation(s)
- Elham Sajjadi
- Division of Pathology, IEO, European Institute of Oncology IRCCS, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Gabriella Gaudioso
- Division of Pathology, Fondazione IRCCS Ca’ Granda—Ospedale Maggiore Policlinico, Milan, Italy
| | - Andrea Terrasi
- Division of Molecular Biology, Biomedical Center, Faculty of Medicine, LMU Munich, Planegg-Martinsried, Munich, Germany
| | - Francesca Boggio
- Division of Pathology, Fondazione IRCCS Ca’ Granda—Ospedale Maggiore Policlinico, Milan, Italy
| | - Konstantinos Venetis
- Division of Pathology, IEO, European Institute of Oncology IRCCS, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Mariia Ivanova
- Division of Pathology, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Letizia Bertolasi
- Division of Pathology, Fondazione IRCCS Ca’ Granda—Ospedale Maggiore Policlinico, Milan, Italy
| | - Gianluca Lopez
- Division of Pathology, Fondazione IRCCS Ca’ Granda—Ospedale Maggiore Policlinico, Milan, Italy
| | - Letterio Runza
- Division of Pathology, Fondazione IRCCS Ca’ Granda—Ospedale Maggiore Policlinico, Milan, Italy
| | - Alice Premoli
- Division of Pathology, Fondazione IRCCS Ca’ Granda—Ospedale Maggiore Policlinico, Milan, Italy
| | - Daniele Lorenzini
- Division of Pathology, Fondazione IRCCS Ca’ Granda—Ospedale Maggiore Policlinico, Milan, Italy
| | - Elena Guerini-Rocco
- Division of Pathology, IEO, European Institute of Oncology IRCCS, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Stefano Ferrero
- Division of Pathology, Fondazione IRCCS Ca’ Granda—Ospedale Maggiore Policlinico, Milan, Italy
- Department of Biomedical, Surgical, and Dental Sciences, University of Milan, Milan, Italy
| | - Valentina Vaira
- Division of Pathology, Fondazione IRCCS Ca’ Granda—Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Nicola Fusco
- Division of Pathology, IEO, European Institute of Oncology IRCCS, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
- *Correspondence: Nicola Fusco,
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Dong Y, Peng N, Dong L, Tan S, Zhang X. Non-coding RNAs: Important participants in cardiac fibrosis. Front Cardiovasc Med 2022; 9:937995. [PMID: 35966549 PMCID: PMC9365961 DOI: 10.3389/fcvm.2022.937995] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 06/24/2022] [Indexed: 11/24/2022] Open
Abstract
Cardiac remodeling is a pathophysiological process activated by diverse cardiac stress, which impairs cardiac function and leads to adverse clinical outcome. This remodeling partly attributes to cardiac fibrosis, which is a result of differentiation of cardiac fibroblasts to myofibroblasts and the production of excessive extracellular matrix within the myocardium. Non-coding RNAs mainly include microRNAs and long non-coding RNAs. These non-coding RNAs have been proved to have a profound impact on biological behaviors of various cardiac cell types and play a pivotal role in the development of cardiac fibrosis. This review aims to summarize the role of microRNAs and long non-coding RNAs in cardiac fibrosis associated with pressure overload, ischemia, diabetes mellitus, aging, atrial fibrillation and heart transplantation, meanwhile shed light on the diagnostic and therapeutic potential of non-coding RNAs for cardiac fibrosis.
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Liu YQ, Luo M, Shi Y, Guo Y, Zhang H, Yang KD, Li TR, Yang LQ, Liu TT, Huang B, Liu Q, He ZC, Zhang XN, Wang WY, Wang S, Zeng H, Niu Q, Zhang X, Cui YH, Zhang ZR, Bian XW, Ping YF. Dicer deficiency impairs proliferation but potentiates anti-tumoral effect of macrophages in glioblastoma. Oncogene 2022; 41:3791-3803. [PMID: 35764885 DOI: 10.1038/s41388-022-02393-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 06/05/2022] [Accepted: 06/16/2022] [Indexed: 11/09/2022]
Abstract
Glioblastoma is a lethal primary brain tumor with abundant immune-suppressive glioblastoma-associated macrophage (GAM) infiltration. Skewing immune suppressive GAMs towards an immune-activating phenotype represents a promising immunotherapeutic strategy against glioblastoma. Herein, we reported that genetic deletion of miRNA-processing enzyme Dicer in macrophages inhibited the growth of GL261 murine glioblastoma xenografts and prolonged survival of tumor-bearing mice. Single cell RNA sequencing (scRNA-seq) of the tumor-infiltrating immune cells revealed that Dicer deletion in macrophages reduced the proportion of cell-cycling GAM cluster and reprogramed the remaining GAMs towards a proinflammatory activation state (enhanced phagocytotic and IFN-producing signature). Dicer-deficient GAMs showed reduced level of cyclin-dependent kinases (CDK1 and CDK2) and increased expression of CDK inhibitor p27 Kip1, thus manifesting impaired proliferation. Dicer knockout enhanced phagocytotic activity of GAMs to eliminate GL261 tumor cells. Increased proinflammatory GAM clusters in macrophage Dicer-deficient mice actively interacted with tumor-infiltrating T cells and NK cells through TNF paracrine signaling to create a pro-inflammatory immune microenvironment for tumor cell elimination. Our work identifies the role of Dicer deletion in macrophages in generating an immune-activating microenvironment, which could be further developed as a potential immunotherapeutic strategy against glioblastoma.
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Affiliation(s)
- Yu-Qi Liu
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.,Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, 400038, China.,Army 953 Hospital, Shigatse Branch of Xinqiao Hospital, Third Military Medical University (Army Medical University), Shigatse, 857000, China
| | - Min Luo
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.,Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, 400038, China
| | - Yu Shi
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.,Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, 400038, China
| | - Ying Guo
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.,Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, 400038, China
| | - Hua Zhang
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.,Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, 400038, China
| | - Kai-Di Yang
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.,Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, 400038, China
| | - Tian-Ran Li
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.,Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, 400038, China
| | - Liu-Qing Yang
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.,Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, 400038, China
| | - Ting-Ting Liu
- Institute of Immunology, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Bo Huang
- Institute of Immunology, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Qing Liu
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.,Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, 400038, China
| | - Zhi-Cheng He
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.,Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, 400038, China
| | - Xiao-Ning Zhang
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.,Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, 400038, China
| | - Wen-Ying Wang
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.,Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, 400038, China
| | - Shuai Wang
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.,Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, 400038, China
| | - Hui Zeng
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.,Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, 400038, China
| | - Qin Niu
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.,Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, 400038, China
| | - Xia Zhang
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.,Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, 400038, China
| | - You-Hong Cui
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.,Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, 400038, China
| | - Zhi-Ren Zhang
- Institute of Immunology, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
| | - Xiu-Wu Bian
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China. .,Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, 400038, China.
| | - Yi-Fang Ping
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China. .,Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, 400038, China.
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40
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Phu TA, Ng M, Vu NK, Bouchareychas L, Raffai RL. IL-4 polarized human macrophage exosomes control cardiometabolic inflammation and diabetes in obesity. Mol Ther 2022; 30:2274-2297. [PMID: 35292359 PMCID: PMC9171286 DOI: 10.1016/j.ymthe.2022.03.008] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 02/25/2022] [Accepted: 03/10/2022] [Indexed: 11/25/2022] Open
Abstract
Cardiometabolic disease is an increasing cause of morbidity and death in society. While M1-like macrophages contribute to metabolic inflammation and insulin resistance, those polarized to an M2-like phenotype exert protective properties. Building on our observations reporting M2-like macrophage exosomes in atherosclerosis control, we tested whether they could serve to control inflammation in the liver and adipose tissue of obese mice. In thinking of clinical translation, we studied human THP-1 macrophages exposed to interleukin (IL)-4 as a source of exosomes (THP1-IL4-exo). Our findings show that THP1-IL4-exo polarized primary macrophages to an anti-inflammatory phenotype and reprogramed their energy metabolism by increasing levels of microRNA-21/99a/146b/378a (miR-21/99a/146b/378a) while reducing miR-33. This increased lipophagy, mitochondrial activity, and oxidative phosphorylation (OXPHOS). THP1-IL4-exo exerted a similar regulation of these miRs in cultured 3T3-L1 adipocytes. This enhanced insulin-dependent glucose uptake through increased peroxisome proliferator activated receptor gamma (PPARγ)-driven expression of GLUT4. It also increased levels of UCP1 and OXPHOS activity, which promoted lipophagy, mitochondrial activity, and beiging of 3T3-L1 adipocytes. Intraperitoneal infusions of THP1-IL4-exo into obese wild-type and Ldlr-/- mice fed a Western high-fat diet reduced hematopoiesis and myelopoiesis, and favorably reprogramed inflammatory signaling and metabolism in circulating Ly6Chi monocytes. This also reduced leukocyte numbers and inflammatory activity in the circulation, aorta, adipose tissue, and the liver. Such treatments reduced hepatic steatosis and increased the beiging of white adipose tissue as revealed by increased UCP1 expression and OXPHOS activity that normalized blood insulin levels and improved glucose tolerance. Our findings support THP1-IL4-exo as a therapeutic approach to control cardiometabolic disease and diabetes in obesity.
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Affiliation(s)
- Tuan Anh Phu
- Department of Veterans Affairs, Surgical Service (112G), San Francisco VA Medical Center, San Francisco, CA 94121, USA; Northern California Institute for Research and Education, San Francisco, CA 94121, USA
| | - Martin Ng
- Department of Veterans Affairs, Surgical Service (112G), San Francisco VA Medical Center, San Francisco, CA 94121, USA; Northern California Institute for Research and Education, San Francisco, CA 94121, USA
| | - Ngan K Vu
- Department of Veterans Affairs, Surgical Service (112G), San Francisco VA Medical Center, San Francisco, CA 94121, USA; Northern California Institute for Research and Education, San Francisco, CA 94121, USA
| | - Laura Bouchareychas
- Department of Veterans Affairs, Surgical Service (112G), San Francisco VA Medical Center, San Francisco, CA 94121, USA; Northern California Institute for Research and Education, San Francisco, CA 94121, USA
| | - Robert L Raffai
- Department of Veterans Affairs, Surgical Service (112G), San Francisco VA Medical Center, San Francisco, CA 94121, USA; Northern California Institute for Research and Education, San Francisco, CA 94121, USA; Department of Surgery, Division of Endovascular and Vascular Surgery, University of California, San Francisco, CA 94143, USA.
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41
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Xue J, Du R, Ling S, Song J, Yuan X, Liu C, Sun W, Li Y, Zhong G, Wang Y, Yuan G, Jin X, Liu Z, Zhao D, Li Y, Xing W, Fan Y, Liu Z, Pan J, Zhen Z, Zhao Y, Yang Q, Li J, Chang YZ, Li Y. Osteoblast Derived Exosomes Alleviate Radiation- Induced Hematopoietic Injury. Front Bioeng Biotechnol 2022; 10:850303. [PMID: 35528209 PMCID: PMC9070646 DOI: 10.3389/fbioe.2022.850303] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 03/30/2022] [Indexed: 12/29/2022] Open
Abstract
As hematopoietic stem cells can differentiate into all hematopoietic lineages, mitigating the damage to hematopoietic stem cells is important for recovery from overdose radiation injury. Cells in bone marrow microenvironment are essential for hematopoietic stem cells maintenance and protection, and many of the paracrine mediators have been discovered in shaping hematopoietic function. Several recent reports support exosomes as effective regulators of hematopoietic stem cells, but the role of osteoblast derived exosomes in hematopoietic stem cells protection is less understood. Here, we investigated that osteoblast derived exosomes could alleviate radiation damage to hematopoietic stem cells. We show that intravenous injection of osteoblast derived exosomes promoted WBC, lymphocyte, monocyte and hematopoietic stem cells recovery after irradiation significantly. By sequencing osteoblast derived exosomes derived miRNAs and verified in vitro, we identified miR-21 is involved in hematopoietic stem cells protection via targeting PDCD4. Collectively, our data demonstrate that osteoblast derived exosomes derived miR-21 is a resultful regulator to radio-protection of hematopoietic stem cells and provide a new strategy for reducing radiation induced hematopoietic injury.
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Affiliation(s)
- Jianqi Xue
- Laboratory of Molecular Iron Metabolism, Key Laboratory of Molecular and Cellular Biology of Ministry of Education, College of Life Science, Hebei Normal University, Shijiazhuang, China.,State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Ruikai Du
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Shukuan Ling
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Jinping Song
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Xinxin Yuan
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Caizhi Liu
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Weijia Sun
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Yuheng Li
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Guohui Zhong
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Yinbo Wang
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Guodong Yuan
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Xiaoyan Jin
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Zizhong Liu
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Dingsheng Zhao
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Youyou Li
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Wenjuan Xing
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Yuanyuan Fan
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Zifan Liu
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Junjie Pan
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Zhen Zhen
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Yunzhang Zhao
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Qinna Yang
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Jianwei Li
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Yan-Zhong Chang
- Laboratory of Molecular Iron Metabolism, Key Laboratory of Molecular and Cellular Biology of Ministry of Education, College of Life Science, Hebei Normal University, Shijiazhuang, China
| | - Yingxian Li
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
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42
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Cong L, Xie X, Liu S, Xiang L, Fu X. Genistein promotes M1 macrophage apoptosis and reduces inflammatory response by disrupting miR-21/TIPE2 pathway. Saudi Pharm J 2022; 30:934-945. [PMID: 35903524 PMCID: PMC9315303 DOI: 10.1016/j.jsps.2022.05.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Accepted: 05/20/2022] [Indexed: 11/29/2022] Open
Abstract
Cardiovascular diseases are a major cause of mortality, and vascular injury, a common pathological basis of cardiovascular disease, is deeply correlated with macrophage apoptosis and inflammatory response. Genistein, a type of phytoestrogen, exerts cardiovascular protective activities, but the underlying mechanism has not been fully elucidated. In this study, RAW264.7 cells were treated with genistein, lipopolysaccharide (LPS), nuclear factor-kappa B (NF-κB) inhibitor, and/or protein kinase B (AKT) agonist to determine the role of genistein in apoptosis and inflammation in LPS-stimulated cells. Simultaneously, high fat diet-fed C57BL/6 mice were administered genistein to evaluate the function of genistein on LPS-induced cardiovascular injury mouse model. Here, we demonstrated that LPS obviously increased apoptosis resistance and inflammatory response of macrophages by promoting miR-21 expression, and miR-21 downregulated tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) expression by targeting the coding region. Genistein reduced miR-21 expression by inhibiting NF-κB, then blocked toll-like receptor 4 (TLR4) pathway and AKT phosphorylation dependent on TIPE2, resulting in inhibition of LPS. Our research suggests that miR-21/TIPE2 pathway is involved in M1 macrophage apoptosis and inflammatory response, and genistein inhibits the progression of LPS-induced cardiovascular injury at the epigenetic level via regulating the promoter region of Vmp1 by NF-κB.
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Affiliation(s)
- Li Cong
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Changsha 410013, China
- School of Medicine, Hunan Normal University, Changsha 410013, China
- Corresponding authors at: School of Medicine, Hunan Normal University, Changsha 410013, China.
| | - Xiaolin Xie
- School of Medicine, Hunan Normal University, Changsha 410013, China
| | - Sujuan Liu
- School of Medicine, Hunan Normal University, Changsha 410013, China
| | - Liping Xiang
- School of Medicine, Hunan Normal University, Changsha 410013, China
| | - Xiaohua Fu
- School of Medicine, Hunan Normal University, Changsha 410013, China
- Corresponding authors at: School of Medicine, Hunan Normal University, Changsha 410013, China.
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Jiang Q, Li Y, Wu Q, Huang L, Xu J, Zeng Q. Pathogenic role of microRNAs in atherosclerotic ischemic stroke: Implications for diagnosis and therapy. Genes Dis 2022; 9:682-696. [PMID: 35782982 PMCID: PMC9243347 DOI: 10.1016/j.gendis.2021.01.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 12/16/2020] [Accepted: 01/04/2021] [Indexed: 12/15/2022] Open
Abstract
Ischemic stroke resulting from atherosclerosis (particularly in the carotid artery) is one of the major subtypes of stroke and has a high incidence of death. Disordered lipid homeostasis, lipid deposition, local macrophage infiltration, smooth muscle cell proliferation, and plaque rupture are the main pathological processes of atherosclerotic ischemic stroke. Hepatocytes, macrophages, endothelial cells and vascular smooth muscle cells are the main cell types participating in these processes. By inhibiting the expression of the target genes in these cells, microRNAs play a key role in regulating lipid disorders and atherosclerotic ischemic stroke. In this article, we listed the microRNAs implicated in the pathology of atherosclerotic ischemic stroke and aimed to explain their pro- or antiatherosclerotic roles. Our article provides an update on the potential diagnostic use of miRNAs for detecting growing plaques and impending clinical events. Finally, we provide a perspective on the therapeutic use of local microRNA delivery and discuss the challenges for this potential therapy.
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miR-21 Regulates Immune Balance Mediated by Th17/Treg in Peripheral Blood of Septic Rats during the Early Phase through Apoptosis Pathway. Biochem Res Int 2022; 2022:9948229. [PMID: 35528843 PMCID: PMC9068307 DOI: 10.1155/2022/9948229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 02/23/2022] [Accepted: 04/08/2022] [Indexed: 11/27/2022] Open
Abstract
Objective To study the mechanism by which miR-21 regulates the differentiation and function of Th17/Treg cells in sepsis. Methods A rat model with sepsis was made by cecal ligation and puncture (CLP). Then, some of the septic rats were transfected with miR-21 mimic or inhibitor by liposome. At 48 hours, lymphocytes and plasma from septic rats were isolated for further experimental detection. The expression of miR-21 in lymphocytes was detected by Polymerase Chain Reaction (PCR); the differentiation of Th17/Treg cells was counted by flow cytometry; lymphocyte apoptosis was observed by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay. The caspase-3/9 proteins were tested by Western blot; IL-10 and IL-17 were detected by enzyme-linked immunosorbent assay (ELISA). Results Compared with the sepsis group (SP group), the Th17 cells increased significantly, the Treg cells decreased significantly, the apoptosis rate of lymphocytes decreased significantly, the mRNA and proteins of caspase-3/9 decreased significantly, the IL-17 decreased, and the IL-10 increased in the sepsis group transfected with miR-21 (SP + miR-21 mimic group). After transfection of miR-21 inhibitor, the results were almost opposite to those of SP + miR-21 mimic group. Conclusions The differentiation and function of Th17/Treg cells were regulated by miR-21 in sepsis through caspase pathway.
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Wang Y, Shi R, Zhai R, Yang S, Peng T, Zheng F, Shen Y, Li M, Li L. Matrix stiffness regulates macrophage polarization in atherosclerosis. Pharmacol Res 2022; 179:106236. [PMID: 35483516 DOI: 10.1016/j.phrs.2022.106236] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 04/01/2022] [Accepted: 04/21/2022] [Indexed: 12/12/2022]
Abstract
Atherosclerosis is a chronic inflammatory disease and the pathological basis of many fatal cardiovascular diseases. Macrophages, the main inflammatory cells in atherosclerotic plaque, have a paradox role in disease progression. In response to different microenvironments, macrophages mainly have two polarized directions: pro-inflammatory macrophages and anti-inflammatory macrophages. More and more evidence shows that macrophage is mechanosensitive and matrix stiffness regulate macrophage phenotypes in atherosclerosis. However, the molecular mechanism of matrix stiffness regulating macrophage polarization still lacks in-depth research, which hinders the development of new anti-atherosclerotic therapies. In this review, we discuss the important role of matrix stiffness in regulating macrophage polarization through mechanical signal transduction (Hippo, Piezo, cytoskeleton, and integrin) and epigenetic mechanisms (miRNA, DNA methylation, and histone). We hope to provide a new perspective for atherosclerosis therapy by targeting matrix stiffness and macrophage polarization.
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Affiliation(s)
- Yin Wang
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, China
| | - Ruotong Shi
- Norman Bethune College of Medicine, Jilin University, Changchun 130021, China
| | - Ran Zhai
- Norman Bethune College of Medicine, Jilin University, Changchun 130021, China
| | - Shiyan Yang
- Norman Bethune College of Medicine, Jilin University, Changchun 130021, China
| | - Tianqi Peng
- Norman Bethune College of Medicine, Jilin University, Changchun 130021, China
| | - Fuwen Zheng
- Norman Bethune College of Medicine, Jilin University, Changchun 130021, China
| | - YanNan Shen
- NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun 130021, China.
| | - Meiying Li
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, China.
| | - Lisha Li
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, China.
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Mahmoudi A, Moadab F, Safdarian E, Navashenaq JG, Rezaee M, Gheibihayat SM. MicroRNAs and Efferocytosis: Implications for Diagnosis and Therapy. Mini Rev Med Chem 2022; 22:2641-2660. [PMID: 35362375 DOI: 10.2174/1389557522666220330150937] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 09/24/2021] [Accepted: 01/19/2022] [Indexed: 11/22/2022]
Abstract
About 10-100 billion cells are generated in the human body in a day, and accordingly, 10-100 billion cells predominantly die for maintaining homeostasis. Dead cells generated by apoptosis are also rapidly engulfed by macrophages (Mθs) to be degraded. In case of the inefficient engulfment of apoptotic cells (ACs) via Mθs, they experience secondary necrosis and thus release intracellular materials, which display damage-associated molecular patterns (DAMPs) and result in diseases. Over the last decades, researchers have also reflected on the significant contribution of microRNAs (miRNAs) to autoimmune diseases through the regulation of Mθs functions. Moreover, miRNAs have shown intricate involvement with completely adjusting basic Mθs functions, such as phagocytosis, inflammation, efferocytosis, tumor promotion, and tissue repair. In this review, the mechanism of efferocytosis containing "Find-Me", "Eat-Me", and "Digest-Me" signals is summarized and the biogenesis of miRNAs is briefly described. Finally, the role of miRNAs in efferocytosis is discussed. It is concluded that miRNAs represent promising treatments and diagnostic targets in impaired phagocytic clearance, which leads to different diseases.
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Affiliation(s)
- Ali Mahmoudi
- Department of medical biotechnology and nanotechnology, faculty of medicine, Mashhad University of Medical science, Iran
| | - Fatemeh Moadab
- Medical student, Student Research Committee, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Esmat Safdarian
- Legal Medicine Research Center, Legal Medicine Organization, Tehran Iran
| | | | - Mehdi Rezaee
- Department of Medical Biotechnology, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran;
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Seyed Mohammad Gheibihayat
- Department of Medical Biotechnology, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
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Target-Dependent Coordinated Biogenesis of Secondary MicroRNAs by miR-146a Balances Macrophage Activation Processes. Mol Cell Biol 2022; 42:e0045221. [PMID: 35311564 PMCID: PMC9022539 DOI: 10.1128/mcb.00452-21] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/04/2022] Open
Abstract
MicroRNAs (miRNAs) repress protein expression by binding to the target mRNAs. Exploring whether the expression of one miRNA can regulate the abundance and activity of other miRNAs, we noted the coordinated biogenesis of miRNAs in activated macrophages. miRNAs with higher numbers of binding sites (the “primary” miRNAs) induce expression of other miRNAs (“secondary” miRNAs) having binding sites on the 3′ untranslated region (UTR) of common target mRNAs. miR-146a-5p, in activated macrophages, acts as a “primary” miRNA that coordinates biogenesis of “secondary” miR-125b, miR-21, or miR-142-3p to target new sets of mRNAs to balance the immune responses. During coordinated biogenesis, primary miRNA drives the biogenesis of secondary miRNA in a target mRNA- and Dicer1 activity-dependent manner. The coordinated biogenesis of miRNAs was observed across different cell types. The target-dependent coordinated miRNA biogenesis also ensures a cumulative mode of action of primary and secondary miRNAs on the secondary target mRNAs. Interestingly, using the “primary” miR-146a-5p-specific inhibitor, we could inhibit the target-dependent biogenesis of secondary miRNAs that can stop the miRNA-mediated buffering of cytokine expression and inflammatory response occurring in activated macrophages. Computational analysis suggests the prevalence of coordinated biogenesis of miRNAs also in other contexts in human and in mouse.
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PDL1-binding peptide/anti-miRNA21 conjugate as a therapeutic modality for PD-L1high tumors and TAMs. J Control Release 2022; 345:62-74. [DOI: 10.1016/j.jconrel.2022.02.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 02/22/2022] [Accepted: 02/23/2022] [Indexed: 11/19/2022]
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Wang Y, Hou M, Duan S, Zhao Z, Wu X, Chen Y, Yin L. Macrophage-targeting gene silencing orchestrates myocardial microenvironment remodeling toward the anti-inflammatory treatment of ischemia-reperfusion (IR) injury. Bioact Mater 2022; 17:320-333. [PMID: 35386446 PMCID: PMC8965030 DOI: 10.1016/j.bioactmat.2022.01.026] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 01/02/2022] [Accepted: 01/18/2022] [Indexed: 01/03/2023] Open
Abstract
Ischemia-reperfusion (IR) injury represents a major cause of myocardial dysfunction after infarction and thrombolytic therapy, and it is closely related to the free radical explosion and overwhelming inflammatory responses. Herein, macrophage-targeting nanocomplexes (NCs) are developed to mediate efficient co-delivery of siRNA against MOF (siMOF) and microRNA-21 (miR21) into myocardial macrophages, cooperatively orchestrating the myocardial microenvironment against IR injury. Bioreducible, branched poly(β-amino ester) (BPAE-SS) is designed to co-condense siMOF and miR21 into NCs in a multivalency-reinforced approach, and they are surface-decorated with carboxylated mannan (Man-COOH) to shield the positive surface charges and enhance the serum stability. The final MBSsm NCs are efficiently internalized by myocardial macrophages after systemic administration, wherein BPAE-SS is degraded into small segments by intracellular glutathione to promote the siMOF/miR21 release, finally provoking efficient gene silencing. Thus, cardiomyocyte protection and macrophage modulation are realized via the combined effects of ROS scavenging, inflammation inhibition, and autophagy attenuation, which ameliorates the myocardial microenvironment and restores the cardiac function via positive cellular crosstalk. This study renders promising solutions to address the multiple systemic barriers against in vivo nucleic acid delivery, and it also offers new options for IR injury by manipulating multiple reciprocal bio-reactions.
Macrophage-targeting and reduction-dissociable NCs mediate efficient siMOF/miR21 co-delivery. siMOF and miR21 cooperatively inhibit ROS production, inflammation, and autophagy. siMOF and miR21 orchestrate microenvironment remodeling via cellular cross-talk. NCs mediate efficient treatment of myocardial ischemia reperfusion injury.
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Jiang Y, Du T. Relation of circulating lncRNA GAS5 and miR-21 with biochemical indexes, stenosis severity, and inflammatory cytokines in coronary heart disease patients. J Clin Lab Anal 2022; 36:e24202. [PMID: 34997773 PMCID: PMC8842157 DOI: 10.1002/jcla.24202] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Revised: 12/10/2021] [Accepted: 12/15/2021] [Indexed: 12/11/2022] Open
Abstract
Background Long noncoding RNA GAS5 (lnc‐GAS5) and its target microRNA‐21 (miR‐21) regulate blood lipid, macrophages, Th cells, vascular smooth muscle cells to participate in atherosclerosis, and related coronary heart disease (CHD). The study aimed to further explore the linkage of their circulating expressions with common biochemical indexes, stenosis severity and inflammatory cytokines in CHD patients. Methods Ninety‐eight CHD patients and 100 controls confirmed by coronary angiography were enrolled. Plasma samples were collected for lnc‐GAS5 and miR‐21 detection by reverse transcription‐quantitative polymerase chain reaction and inflammatory cytokines determination by enzyme‐linked immunosorbent assay. Results Lnc‐GAS5 was increased in CHD patients compared with controls (2.270 (interquartile range [IQR]: 1.676–3.389) vs. 0.999 ([IQR: 0.602–1.409], p < 0.001), whereas miR‐21 showed opposite tread (0.442 [IQR: 0.318–0.698] vs. 0.997 [IQR: 0.774–1.368], p < 0.001). In aspect of their intercorrelation, lnc‐GAS5 negatively linked with miR‐21 in CHD patients (p < 0.001) instead of controls (p = 0.211). Interestingly, among the common biochemical indexes, lnc‐GAS5 related to decreased high‐density lipoprotein cholesterol (p = 0.008) and increased C‐reactive protein (CRP) (p < 0.001), while miR‐21 correlated with lower total cholesterol (p = 0.024) and CRP (p < 0.001) in CHD patients. As stenosis degree, lnc‐GAS5 positively correlated with Gensini score (p < 0.001), but miR‐21 exhibited negative association (p = 0.003) in CHD patients. In terms of inflammatory cytokines, lnc‐GAS5 positively related to tumor necrosis factor α (TNF‐α) and interleukin (IL)‐17A, while miR‐21 negatively linked with TNF‐α, IL‐1β, IL‐6, and IL‐17 in CHD patients (all p < 0.05). Conclusion Circulating lnc‐GAS5 and its target miR‐21 exhibit potency to serve as biomarkers for CHD management.
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Affiliation(s)
- Yan Jiang
- Department of Nosocomial Infection Management, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Edong Healthcare Group, Huangshi, China
| | - Tian Du
- Department of Thoracic and Cardiovascular Surgery, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Edong Healthcare Group, Huangshi, China
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