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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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Majumdar N, Pokharel BR, Dickerson A, Cruceanu A, Rajput S, Pokhrel LR, Cook PP, Akula SM. The miRNomics of antiretroviral therapy-induced obesity. Funct Integr Genomics 2025; 25:81. [PMID: 40186666 PMCID: PMC11972218 DOI: 10.1007/s10142-025-01585-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 03/17/2025] [Accepted: 03/18/2025] [Indexed: 04/07/2025]
Abstract
Human immunodeficiency virus (HIV) is a retrovirus that incorporates its genetic material into the host's chromosome. The resulting diseases and related conditions constitute a global health problem as there are no treatments to eliminate HIV from an infected individual. However, the potent, complex, and active antiretroviral therapy (ART) strategies have been able to successfully inhibit HIV replication in patients. Unfortunately, obesity following ART is frequent among HIV-infected patients. The mechanism underlying ART-induced obesity is characterized based on expression of traditional markers such as genes and proteins. However, little is known about, yet another key component of molecular biology known as microRNAs (miRNAs). Micro-RNAs are ~ 22 base-long non-coding nucleotides capable of regulating more than 60% of all human protein-coding genes. The interest in miRNA molecules is increasing and their roles in HIV and obesity are beginning to be apparent. In this review, we provide an overview of HIV and its associated diseases, ART-induced obesity, and discuss the roles and plausible benefits of miRNAs in regulating obesity genes in HIV-infected patients. Understanding the roles of miRNAs in ART-induced obesity will aid in tracking the disease progression and designing beneficial therapeutic approaches.
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Affiliation(s)
- Niska Majumdar
- Department of Microbiology & Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, 27834, USA
| | - Bishwa R Pokharel
- Department of Microbiology & Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, 27834, USA
| | - Abigail Dickerson
- Department of Microbiology & Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, 27834, USA
| | - Andreea Cruceanu
- Department of Microbiology & Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, 27834, USA
| | - Smit Rajput
- Department of Internal Medicine, Brody School of Medicine at East Carolina University, Greenville, NC, 27834, USA
| | - Lok R Pokhrel
- Department of Public Health, Brody School of Medicine at East Carolina University, Greenville, NC, 27834, USA
| | - Paul P Cook
- Department of Internal Medicine, Brody School of Medicine at East Carolina University, Greenville, NC, 27834, USA.
| | - Shaw M Akula
- Department of Microbiology & Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, 27834, USA.
- Department of Internal Medicine, Brody School of Medicine at East Carolina University, Greenville, NC, 27834, USA.
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Huang K, Pokhrel A, Echesabal-Chen J, Scott J, Bruce T, Jo H, Stamatikos A. Inhibiting MiR-33a-3p Expression Fails to Enhance ApoAI-Mediated Cholesterol Efflux in Pro-Inflammatory Endothelial Cells. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:329. [PMID: 40005445 PMCID: PMC11857470 DOI: 10.3390/medicina61020329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Revised: 02/08/2025] [Accepted: 02/11/2025] [Indexed: 02/27/2025]
Abstract
Background and Objectives: Atherosclerosis is an inflammatory condition that results in cholesterol accumulating within vessel wall cells. Atherosclerotic cardiovascular disease is the leading cause of mortality worldwide due to this disease being a major contributor to myocardial infarctions and cerebrovascular accidents. Research suggests that cholesterol accumulation occurring precisely within arterial endothelial cells triggers atherogenesis and exacerbates atherosclerosis. Furthermore, inflamed endothelium acts as a catalyst for atherosclerotic development. Therefore, enhancing cholesterol removal specifically in pro-inflammatory endothelial cells may be a potential treatment option for atherosclerosis. While we have previously shown that inhibiting the microRNA guide strand miR-33a-5p within pro-inflammatory endothelial cells increases both ABCA1 expression and apoAI-mediated cholesterol efflux, it is unknown whether inhibiting the miR-33a-3p passenger strand in pro-inflammatory endothelial cells causes similar atheroprotective effects. In this study, this is what we aimed to test. Materials and Methods: We used plasmid transfection to knockdown miR-33a-3p expression within cultured pro-inflammatory immortalized mouse aortic endothelial cells (iMAECs). We compared ABCA1 expression and apoAI-mediated cholesterol efflux within these cells to cultured pro-inflammatory iMAECs transfected with a control plasmid. Results: The knockdown of miR-33a-3p expression within pro-inflammatory iMAECs resulted in a significant increase in ABCA1 mRNA expression. However, the inhibition of miR-33a-3p did not significantly increase ABCA1 protein expression within pro-inflammatory iMAECs. Moreover, we failed to detect a significant increase in apoAI-mediated cholesterol efflux within pro-inflammatory iMAECs from miR-33a-3p knockdown. Conclusions: Our results indicative that the knockdown of miR-33a-3p alone does not enhance ABCA1-dependent cholesterol efflux within pro-inflammatory endothelial cells. To gain any atheroprotective benefit from inhibiting miR-33a-3p within pro-inflammatory endothelium, additional anti-atherogenic strategies would likely be needed in unison.
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Affiliation(s)
- Kun Huang
- Department of Food, Nutrition, and Packaging Sciences, Clemson University, Clemson, SC 29634, USA; (K.H.); (A.P.); (J.E.-C.)
| | - Achala Pokhrel
- Department of Food, Nutrition, and Packaging Sciences, Clemson University, Clemson, SC 29634, USA; (K.H.); (A.P.); (J.E.-C.)
| | - Jing Echesabal-Chen
- Department of Food, Nutrition, and Packaging Sciences, Clemson University, Clemson, SC 29634, USA; (K.H.); (A.P.); (J.E.-C.)
| | - Justin Scott
- Clemson Light Imaging Facility, Clemson University, Clemson, SC 29634, USA; (J.S.); (T.B.)
| | - Terri Bruce
- Clemson Light Imaging Facility, Clemson University, Clemson, SC 29634, USA; (J.S.); (T.B.)
| | - Hanjoong Jo
- Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30322, USA;
| | - Alexis Stamatikos
- Department of Food, Nutrition, and Packaging Sciences, Clemson University, Clemson, SC 29634, USA; (K.H.); (A.P.); (J.E.-C.)
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Masoumi-Ardakani Y, Eghbalian M, Fallah H, Jafari A, Shahouzehi B. Exploring serum miR-33b as a novel diagnostic marker for hypercholesterolemia and obesity: insights from a pilot case-control study. BMC Endocr Disord 2025; 25:27. [PMID: 39885530 PMCID: PMC11781059 DOI: 10.1186/s12902-025-01849-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Accepted: 01/20/2025] [Indexed: 02/01/2025] Open
Abstract
Obesity and atherosclerosis are significant metabolic diseases characterized by disrupted lipid metabolism. MicroRNAs (miRNAs) are small, conserved, non-coding RNA sequences consisting of approximately 22 nucleotides, playing crucial roles in biological and pathological functions. Among these, miR-33a/b is particularly associated with metabolic diseases, notably obesity and atherosclerosis. In this pilot case-control study, 45 subjects were examined, and serum miR-33b levels were measured in three groups: a control group, hypercholesterolemic (HC) subjects without obesity (HC group), and obese subjects without hypercholesterolemia (obese group). Serum miR-33b levels were determined using the real-time PCR method. The expression of miR-33b was significantly higher in the HC and obese groups compared to the control group (p < 0.001). The Body mass index (BMI) in the obese group was significantly higher than in the control and HC groups (p < 0.001). Additionally, serum total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-c) levels were higher in the HC group compared to both the control and obese groups. Our study demonstrated a correlation between serum miR-33b levels and HC and obesity. Finally, the ROC analysis demonstrated that miR-33b had an AUC of 0.74 for identifying hypercholesterolemia and an AUC of 0.76 for identifying obesity, indicating its acceptable diagnostic value alongside traditional markers. Therefore, serum miR-33b levels can be considered as a potential biomarker for obesity and hypercholesterolemia, but these finding are preliminary and further investigation is necessary in larger samples to confirm these associations.
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Affiliation(s)
- Yaser Masoumi-Ardakani
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Mostafa Eghbalian
- Neuromuscular Rehabilitation Research Centre, Semnan University of Medical Sciences, Semnan, Iran
| | - Hossein Fallah
- Cardiovascular Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran
| | - Alireza Jafari
- Department of Community Nutrition, School of Nutrition Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Beydolah Shahouzehi
- Gastroenterology and Hepatology Research Center, Institute of Basic and Clinical Physiology Sciences, of Clinical Biochemistry, Kerman University of Medical Sciences, Jahad Boulevard Avicenna Avenue, Kerman, 7619813159, Iran.
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Li YY, Chen HR, Yang Y, Pan YJ, Yuan QC, Liu YZ. Murine exosomal miR-30a aggravates cardiac function after acute myocardial infarction via regulating cell fate of cardiomyocytes and cardiac resident macrophages. Int J Cardiol 2024; 414:132395. [PMID: 39074620 DOI: 10.1016/j.ijcard.2024.132395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 07/02/2024] [Accepted: 07/24/2024] [Indexed: 07/31/2024]
Abstract
After acute myocardial infarction (AMI), intercellular communication is crucial for maintaining cardiac homeostasis and patient survival. Exosomes secreted by cardiomyocytes serve as carriers for transporting microRNA(miRNAs), participating in intercellular signaling and the regulation of cardiac function. This study aims to investigate the role of exosomal microRNA-30a(miR-30a) during AMI and its underlying mechanisms. AMI was induced by permanent ligation of the left anterior descending (LAD) artery in C57BL/6 mice. The expression of miR-30a in mice was respectively enhanced and inhibited by administering agomiR-30a and antagomiR-30a. Using HL-1 cardiomyocytes and RAW264.7 macrophages for in vitro experiments, HL-1 cardiomyocytes were cultured under hypoxic conditions to induce ischemic injury. Following isolation and injection of exosomals, a variety of validation methods were utilized to assess the expression of miR-30a, and investigate the effects of enriched exosomal miR-30a on the state of cardiomyocytes. After AMI, the level of exosomal miR-30a in the serum of mice significantly increased and was highly enriched in cardiac tissue. Cardiomyocytes treated with agomiR-30a and miR-30a-enriched exosomes exhibited inhibition of cell autophagy, increased cell apoptosis, mice showed an larger myocardial infarct area and poorer cardiac function. Exosomes released from hypoxic cardiomyocytes transferred miR-30a to cardiac resident macrophages, promoting the polarization into pro-inflammatory M1 macrophages. In conclusion, murine exosomal miR-30a exacerbates cardiac dysfunction post-AMI by disrupting the autophagy-apoptosis balance in cardiomyocytes and polarizing cardiac resident macrophages into pro-inflammatory M1 macrophages. Modulating the expression of miR-30a may reduce cardiac damage following AMI, and targeting exosomal miR-30a could be a potential therapeutic approach for AMI.
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Affiliation(s)
- Ying-Ying Li
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
| | - Hong-Rui Chen
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Yan Yang
- Department of General, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430030, China
| | - Ya-Jie Pan
- Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430022, China
| | - Qing-Chen Yuan
- Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville, Florida, USA
| | - Yu-Zhou Liu
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
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Liu C, Pan X, Hao Z, Wang X, Wang C, Song G. Resveratrol suppresses hepatic fatty acid synthesis and increases fatty acid β-oxidation via the microRNA-33/SIRT6 signaling pathway. Exp Ther Med 2024; 28:326. [PMID: 38979023 PMCID: PMC11229395 DOI: 10.3892/etm.2024.12615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Accepted: 02/23/2024] [Indexed: 07/10/2024] Open
Abstract
Hyperlipidemia is a strong risk factor for numerous diseases. Resveratrol (Res) is a non-flavonoid polyphenol organic compound with multiple biological functions. However, the specific molecular mechanism and its role in hepatic lipid metabolism remain unclear. Therefore, the aim of the present study was to elucidate the mechanism underlying how Res improves hepatic lipid metabolism by decreasing microRNA-33 (miR-33) levels. First, blood miR-33 expression in participants with hyperlipidemia was detected by reverse transcription-quantitative PCR, and the results revealed significant upregulation of miR-33 expression in hyperlipidemia. Additionally, after transfection of HepG2 cells with miR-33 mimics or inhibitor, western blot analysis indicated downregulation and upregulation, respectively, of the mRNA and protein expression levels of sirtuin 6 (SIRT6). Luciferase reporter analysis provided further evidence for binding of miR-33 with the SIRT6 3'-untranslated region. Furthermore, the levels of peroxisome proliferator-activated receptor-γ (PPARγ), PPARγ-coactivator 1α and carnitine palmitoyl transferase 1 were increased, while the concentration levels of acetyl-CoA carboxylase, fatty acid synthase and sterol regulatory element-binding protein 1 were decreased when SIRT6 was overexpressed. Notably, Res improved the basic metabolic parameters of mice fed a high-fat diet by regulating the miR-33/SIRT6 signaling pathway. Thus, it was demonstrated that the dysregulation of miR-33 could lead to lipid metabolism disorders, while Res improved lipid metabolism by regulating the expression of miR-33 and its target gene, SIRT6. Thus, Res can be used to prevent or treat hyperlipidemia and associated diseases clinically by suppressing hepatic fatty acid synthesis and increasing fatty acid β-oxidation.
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Affiliation(s)
- Chunqiao Liu
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
- Hebei Key Laboratory of Metabolic Diseases, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
| | - Xinyan Pan
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
- Hebei Key Laboratory of Metabolic Diseases, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
| | - Zhihua Hao
- Department of Health Care, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
| | - Xing Wang
- Hebei Key Laboratory of Metabolic Diseases, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
| | - Chao Wang
- Hebei Key Laboratory of Metabolic Diseases, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
| | - Guangyao Song
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
- Hebei Key Laboratory of Metabolic Diseases, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
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Aravindraja C, Jeepipalli S, Duncan WD, Vekariya KM, Rahaman SO, Chan EKL, Kesavalu L. Streptococcus gordonii Supragingival Bacterium Oral Infection-Induced Periodontitis and Robust miRNA Expression Kinetics. Int J Mol Sci 2024; 25:6217. [PMID: 38892405 PMCID: PMC11172800 DOI: 10.3390/ijms25116217] [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: 04/30/2024] [Revised: 05/24/2024] [Accepted: 05/28/2024] [Indexed: 06/21/2024] Open
Abstract
Streptococcus gordonii (S. gordonii, Sg) is one of the early colonizing, supragingival commensal bacterium normally associated with oral health in human dental plaque. MicroRNAs (miRNAs) play an important role in the inflammation-mediated pathways and are involved in periodontal disease (PD) pathogenesis. PD is a polymicrobial dysbiotic immune-inflammatory disease initiated by microbes in the gingival sulcus/pockets. The objective of this study is to determine the global miRNA expression kinetics in S. gordonii DL1-infected C57BL/6J mice. All mice were randomly divided into four groups (n = 10 mice/group; 5 males and 5 females). Bacterial infection was performed in mice at 8 weeks and 16 weeks, mice were euthanized, and tissues harvested for analysis. We analyzed differentially expressed (DE) miRNAs in the mandibles of S. gordonii-infected mice. Gingival colonization/infection by S. gordonii and alveolar bone resorption (ABR) was confirmed. All the S. gordonii-infected mice at two specific time points showed bacterial colonization (100%) in the gingival surface, and a significant increase in mandible and maxilla ABR (p < 0.0001). miRNA profiling revealed 191 upregulated miRNAs (miR-375, miR-34b-5p) and 22 downregulated miRNAs (miR-133, miR-1224) in the mandibles of S. gordonii-infected mice at the 8-week mark. Conversely, at 16 weeks post-infection, 10 miRNAs (miR-1902, miR-203) were upregulated and 32 miRNAs (miR-1937c, miR-720) were downregulated. Two miRNAs, miR-210 and miR-423-5p, were commonly upregulated, and miR-2135 and miR-145 were commonly downregulated in both 8- and 16-week-infected mice mandibles. Furthermore, we employed five machine learning (ML) algorithms to assess how the number of miRNA copies correlates with S. gordonii infections in mice. In the ML analyses, miR-22 and miR-30c (8-week), miR-720 and miR-339-5p (16-week), and miR-720, miR-22, and miR-339-5p (combined 8- and 16-week) emerged as the most influential miRNAs.
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Affiliation(s)
- Chairmandurai Aravindraja
- Department of Periodontology, College of Dentistry, University of Florida, Gainesville, FL 32610, USA; (C.A.); (S.J.); (K.M.V.)
| | - Syam Jeepipalli
- Department of Periodontology, College of Dentistry, University of Florida, Gainesville, FL 32610, USA; (C.A.); (S.J.); (K.M.V.)
| | - William D. Duncan
- Department of Community Dentistry and Behavioral Science, College of Dentistry, University of Florida, Gainesville, FL 32610, USA;
| | - Krishna Mukesh Vekariya
- Department of Periodontology, College of Dentistry, University of Florida, Gainesville, FL 32610, USA; (C.A.); (S.J.); (K.M.V.)
| | - Shaik O. Rahaman
- Department of Nutrition and Food Science, University of Maryland, College Park, MD 20742, USA;
| | - Edward K. L. Chan
- Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, FL 32610, USA;
| | - Lakshmyya Kesavalu
- Department of Periodontology, College of Dentistry, University of Florida, Gainesville, FL 32610, USA; (C.A.); (S.J.); (K.M.V.)
- Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, FL 32610, USA;
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Oladosu O, Chin E, Barksdale C, Powell RR, Bruce T, Stamatikos A. Inhibition of miR-33a-5p in Macrophage-like Cells In Vitro Promotes apoAI-Mediated Cholesterol Efflux. PATHOPHYSIOLOGY 2024; 31:117-126. [PMID: 38535619 PMCID: PMC10976131 DOI: 10.3390/pathophysiology31010009] [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: 01/19/2024] [Revised: 02/25/2024] [Accepted: 02/27/2024] [Indexed: 04/01/2024] Open
Abstract
Atherosclerosis is caused by cholesterol accumulation within arteries. The intima is where atherosclerotic plaque accumulates and where lipid-laden foam cells reside. Intimal foam cells comprise of both monocyte-derived macrophages and macrophage-like cells (MLC) of vascular smooth muscle cell (VSMC) origin. Foam cells can remove cholesterol via apoAI-mediated cholesterol efflux and this process is regulated by the transporter ABCA1. The microRNA miR-33a-5p is thought to be atherogenic via silencing ABCA1 which promotes cholesterol retention and data has shown inhibiting miR-33a-5p in macrophages may be atheroprotective via enhancing apoAI-mediated cholesterol efflux. However, it is not entirely elucidated whether precisely inhibiting miR-33a-5p in MLC also increases ABCA1-dependent cholesterol efflux. Therefore, the purpose of this work is to test the hypothesis that inhibition of miR-33a-5p in cultured MLC enhances apoAI-mediated cholesterol efflux. In our study, we utilized the VSMC line MOVAS cells in our experiments, and cholesterol-loaded MOVAS cells to convert this cell line into MLC. Inhibition of miR-33a-5p was accomplished by transducing cells with a lentivirus that expresses an antagomiR directed at miR-33a-5p. Expression of miR-33a-5p was analyzed by qRT-PCR, ABCA1 protein expression was assessed via immunoblotting, and apoAI-mediated cholesterol efflux was measured using cholesterol efflux assays. In our results, we demonstrated that lentiviral vector-mediated knockdown of miR-33a-5p resulted in decreasing expression of this microRNA in cultured MLC. Moreover, reduction of miR-33a-5p in cultured MLC resulted in de-repression of ABCA1 expression, which caused ABCA1 protein upregulation in cultured MLC. Additionally, this increase in ABCA1 protein expression resulted in enhancing ABCA1-dependent cholesterol efflux through increasing apoAI-mediated cholesterol efflux in cultured MLC. From these findings, we conclude that inhibiting miR-33a-5p in MLC may protect against atherosclerosis by promoting ABCA1-dependent cholesterol efflux.
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Affiliation(s)
- Olanrewaju Oladosu
- Department of Food, Nutrition, and Packaging Sciences, Clemson University, Clemson, SC 29634, USA; (O.O.); (E.C.); (C.B.)
| | - Emma Chin
- Department of Food, Nutrition, and Packaging Sciences, Clemson University, Clemson, SC 29634, USA; (O.O.); (E.C.); (C.B.)
| | - Christian Barksdale
- Department of Food, Nutrition, and Packaging Sciences, Clemson University, Clemson, SC 29634, USA; (O.O.); (E.C.); (C.B.)
| | - Rhonda R. Powell
- Clemson Light Imaging Facility, Clemson University, Clemson, SC 29634, USA; (R.R.P.); (T.B.)
| | - Terri Bruce
- Clemson Light Imaging Facility, Clemson University, Clemson, SC 29634, USA; (R.R.P.); (T.B.)
| | - Alexis Stamatikos
- Department of Food, Nutrition, and Packaging Sciences, Clemson University, Clemson, SC 29634, USA; (O.O.); (E.C.); (C.B.)
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9
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Wang X, Chen Y, Meng H, Meng F. SREBPs as the potential target for solving the polypharmacy dilemma. Front Physiol 2024; 14:1272540. [PMID: 38269061 PMCID: PMC10806128 DOI: 10.3389/fphys.2023.1272540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 12/26/2023] [Indexed: 01/26/2024] Open
Abstract
The phenomenon of polypharmacy is a common occurrence among older people with multiple health conditions due to the rapid increase in population aging and the popularization of clinical guidelines. The prevalence of metabolic syndrome is growing quickly, representing a serious threat to both the public and the worldwide healthcare systems. In addition, it enhances the risk of cardiovascular disease as well as mortality and morbidity. Sterol regulatory element binding proteins (SREBPs) are basic helix-loop-helix leucine zipper transcription factors that transcriptionally modulate genes that regulate lipid biosynthesis and uptake, thereby serving an essential role in biological systems regulation. In this article, we have described the structure of SREBPs and explored their activation and regulation of signals. We also reveal that SREBPs are intricately involved in the modulation of metabolic diseases and thus have tremendous potential as the novel target for single-drug therapy for multiple diseases.
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Affiliation(s)
| | | | | | - Fanbo Meng
- Jilin Provincial Precision Medicine Key Laboratory for Cardiovascular Genetic Diagnosis (Jilin Provincial Engineering Laboratory for Endothelial Function and Genetic Diagnosis of Cardiovascular Disease, Jilin Provincial Molecular Biology Research Center for Precision Medicine of Major Cardiovascular Disease, Jilin Provincial Cardiovascular Research Institute), Department of Cardiology, China-Japan Union Hospital of Jilin University, Changchun, China
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10
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Montaño-Samaniego M, Sánchez-Cedillo J, Lucas-González A, Bravo-Estupiñan DM, Alarcón-Hernández E, Rivera-Gutiérrez S, Balderas-López JA, Ibáñez-Hernández M. Targeted Expression to Liver of an antimiR-33 Sponge as a Gene Therapy Strategy against Hypercholesterolemia: In Vitro Study. Curr Issues Mol Biol 2023; 45:7043-7057. [PMID: 37754229 PMCID: PMC10527677 DOI: 10.3390/cimb45090445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 08/12/2023] [Accepted: 08/17/2023] [Indexed: 09/28/2023] Open
Abstract
Atherosclerosis is the leading cause of cardiovascular diseases in Mexico and worldwide. The membrane transporters ABCA1 and ABCG1 are involved in the reverse transport of cholesterol and stimulate the HDL synthesis in hepatocytes, therefore the deficiency of these transporters promotes the acceleration of atherosclerosis. MicroRNA-33 (miR-33) plays an important role in lipid metabolism and exerts a negative regulation on the transporters ABCA1 and ABCG1. It is known that by inhibiting the function of miR-33 with antisense RNA, HDL levels increase and atherogenic risk decreases. Therefore, in this work, a genetic construct, pPEPCK-antimiR-33-IRES2-EGFP, containing a specific antimiR-33 sponge with two binding sites for miR-33 governed under the PEPCK promoter was designed, constructed, and characterized, the identity of which was confirmed by enzymatic restriction, PCR, and sequencing. Hep G2 and Hek 293 FT cell lines, as well as a mouse hepatocyte primary cell culture were transfected with this plasmid construction showing expression specificity of the PEPCK promoter in hepatic cells. An analysis of the relative expression of miR-33 target messengers showed that the antimiR-33 sponge indirectly induces the expression of its target messengers (ABCA1 and ABCG1). This strategy could open new specific therapeutic options for hypercholesterolemia and atherosclerosis, by blocking the miR-33 specifically in hepatocytes.
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Affiliation(s)
- Mariela Montaño-Samaniego
- Laboratorio de Terapia Génica, Departamento de Bioquímica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City 11340, Mexico; (M.M.-S.); (J.S.-C.); (A.L.-G.); (D.M.B.-E.)
- Laboratorio de Técnicas Fototérmicas, Departamento de Ciencias Básicas, Unidad Politécnica Interdisciplinaria de Biotecnología, Instituto Politécnico Nacional, Mexico City 07340, Mexico;
| | - Jorge Sánchez-Cedillo
- Laboratorio de Terapia Génica, Departamento de Bioquímica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City 11340, Mexico; (M.M.-S.); (J.S.-C.); (A.L.-G.); (D.M.B.-E.)
| | - Amellalli Lucas-González
- Laboratorio de Terapia Génica, Departamento de Bioquímica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City 11340, Mexico; (M.M.-S.); (J.S.-C.); (A.L.-G.); (D.M.B.-E.)
| | - Diana M. Bravo-Estupiñan
- Laboratorio de Terapia Génica, Departamento de Bioquímica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City 11340, Mexico; (M.M.-S.); (J.S.-C.); (A.L.-G.); (D.M.B.-E.)
- Laboratorio de Quimiosensibilidad Tumoral, Facultad de Microbiología, Universidad de Costa Rica, San Jose 11501-2060, Costa Rica
| | - Ernesto Alarcón-Hernández
- Laboratorio de Genética Molecular, Departamento de Bioquímica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City 11340, Mexico;
| | - Sandra Rivera-Gutiérrez
- Laboratorio de Microbiología Molecular, Departamento de Microbiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City 11340, Mexico;
| | - José Abraham Balderas-López
- Laboratorio de Técnicas Fototérmicas, Departamento de Ciencias Básicas, Unidad Politécnica Interdisciplinaria de Biotecnología, Instituto Politécnico Nacional, Mexico City 07340, Mexico;
| | - Miguel Ibáñez-Hernández
- Laboratorio de Terapia Génica, Departamento de Bioquímica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City 11340, Mexico; (M.M.-S.); (J.S.-C.); (A.L.-G.); (D.M.B.-E.)
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11
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Butnariu LI, Gorduza EV, Țarcă E, Pânzaru MC, Popa S, Stoleriu S, Lupu VV, Lupu A, Cojocaru E, Trandafir LM, Moisă ȘM, Florea A, Stătescu L, Bădescu MC. Current Data and New Insights into the Genetic Factors of Atherogenic Dyslipidemia Associated with Metabolic Syndrome. Diagnostics (Basel) 2023; 13:2348. [PMID: 37510094 PMCID: PMC10378477 DOI: 10.3390/diagnostics13142348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 07/06/2023] [Accepted: 07/10/2023] [Indexed: 07/30/2023] Open
Abstract
Atherogenic dyslipidemia plays a critical role in the development of metabolic syndrome (MetS), being one of its major components, along with central obesity, insulin resistance, and hypertension. In recent years, the development of molecular genetics techniques and extended analysis at the genome or exome level has led to important progress in the identification of genetic factors (heritability) involved in lipid metabolism disorders associated with MetS. In this review, we have proposed to present the current knowledge related to the genetic etiology of atherogenic dyslipidemia, but also possible challenges for future studies. Data from the literature provided by candidate gene-based association studies or extended studies, such as genome-wide association studies (GWAS) and whole exome sequencing (WES,) have revealed that atherogenic dyslipidemia presents a marked genetic heterogeneity (monogenic or complex, multifactorial). Despite sustained efforts, many of the genetic factors still remain unidentified (missing heritability). In the future, the identification of new genes and the molecular mechanisms by which they intervene in lipid disorders will allow the development of innovative therapies that act on specific targets. In addition, the use of polygenic risk scores (PRS) or specific biomarkers to identify individuals at increased risk of atherogenic dyslipidemia and/or other components of MetS will allow effective preventive measures and personalized therapy.
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Affiliation(s)
- Lăcramioara Ionela Butnariu
- Department of Medical Genetics, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Eusebiu Vlad Gorduza
- Department of Medical Genetics, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Elena Țarcă
- Department of Surgery II-Pediatric Surgery, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Monica-Cristina Pânzaru
- Department of Medical Genetics, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Setalia Popa
- Department of Medical Genetics, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Simona Stoleriu
- Odontology-Periodontology, Fixed Prosthesis Department, Faculty of Dental Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Vasile Valeriu Lupu
- Department of Pediatrics, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Ancuta Lupu
- Department of Pediatrics, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Elena Cojocaru
- Department of Morphofunctional Sciences I, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Laura Mihaela Trandafir
- Department of Pediatrics, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Ștefana Maria Moisă
- Department of Pediatrics, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Andreea Florea
- Department of Medical Genetics, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Laura Stătescu
- Medical III Department, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Minerva Codruța Bădescu
- III Internal Medicine Clinic, "St. Spiridon" County Emergency Clinical Hospital, 1 Independence Boulevard, 700111 Iasi, Romania
- Department of Internal Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
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12
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Galindo CL, Khan S, Zhang X, Yeh YS, Liu Z, Razani B. Lipid-laden foam cells in the pathology of atherosclerosis: shedding light on new therapeutic targets. Expert Opin Ther Targets 2023; 27:1231-1245. [PMID: 38009300 PMCID: PMC10843715 DOI: 10.1080/14728222.2023.2288272] [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: 06/28/2023] [Accepted: 11/22/2023] [Indexed: 11/28/2023]
Abstract
INTRODUCTION Lipid-laden foam cells within atherosclerotic plaques are key players in all phases of lesion development including its progression, necrotic core formation, fibrous cap thinning, and eventually plaque rupture. Manipulating foam cell biology is thus an attractive therapeutic strategy at early, middle, and even late stages of atherosclerosis. Traditional therapies have focused on prevention, especially lowering plasma lipid levels. Despite these interventions, atherosclerosis remains a major cause of cardiovascular disease, responsible for the largest numbers of death worldwide. AREAS COVERED Foam cells within atherosclerotic plaques are comprised of macrophages, vascular smooth muscle cells, and other cell types which are exposed to high concentrations of lipoproteins accumulating within the subendothelial intimal layer. Macrophage-derived foam cells are particularly well studied and have provided important insights into lipid metabolism and atherogenesis. The contributions of foam cell-based processes are discussed with an emphasis on areas of therapeutic potential and directions for drug development. EXERT OPINION As key players in atherosclerosis, foam cells are attractive targets for developing more specific, targeted therapies aimed at resolving atherosclerotic plaques. Recent advances in our understanding of lipid handling within these cells provide insights into how they might be manipulated and clinically translated to better treat atherosclerosis.
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Affiliation(s)
- Cristi L. Galindo
- Vascular Medicine Institute, Department of Medicine, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA
| | - Saifur Khan
- Vascular Medicine Institute, Department of Medicine, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA
| | - Xiangyu Zhang
- Vascular Medicine Institute, Department of Medicine, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA
| | - Yu-Sheng Yeh
- Vascular Medicine Institute, Department of Medicine, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA
| | - Ziyang Liu
- Vascular Medicine Institute, Department of Medicine, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA
| | - Babak Razani
- Vascular Medicine Institute, Department of Medicine, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA
- Pittsburgh VA Medical Center, Pittsburgh, PA
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13
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Esobi IC, Oladosu O, Echesabal-Chen J, Powell RR, Bruce T, Stamatikos A. miR-33a Expression Attenuates ABCA1-Dependent Cholesterol Efflux and Promotes Macrophage-Like Cell Transdifferentiation in Cultured Vascular Smooth Muscle Cells. J Lipids 2023; 2023:8241899. [PMID: 37359759 PMCID: PMC10289877 DOI: 10.1155/2023/8241899] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 04/08/2023] [Accepted: 06/06/2023] [Indexed: 06/28/2023] Open
Abstract
Recent evidence suggests that the majority of cholesterol-laden cells found in atherosclerotic lesions are vascular smooth muscle cells (VSMC) that have transdifferentiated into macrophage-like cells (MLC). Furthermore, cholesterol-laden MLC of VSMC origin have demonstrated impaired ABCA1-dependent cholesterol efflux, but it is poorly understood why this occurs. A possible mechanism which may at least partially be attributed to cholesterol-laden MLC demonstrating attenuated ABCA1-dependent cholesterol efflux is a miR-33a expression, as a primary function of this microRNA is to silence ABCA1 expression, but this has yet to be rigorously investigated. Therefore, the VSMC line MOVAS cells were used to generate miR-33a knockout (KO) MOVAS cells, and we used KO and wild-type (WT) MOVAS cells to delineate any possible proatherogenic role of miR-33a expression in VSMC. When WT and KO MOVAS cells were cholesterol-loaded to convert into MLC, this resulted in the WT MOVAS cells to exhibit impaired ABCA1-dependent cholesterol efflux. In the cholesterol-loaded WT MOVAS MLC, we also observed a delayed restoration of the VSMC phenotype when these cells were exposed to the ABCA1 cholesterol acceptor, apoAI. These results imply that miR-33a expression in VSMC drives atherosclerosis by triggering MLC transdifferentiation via attenuated ABCA1-dependent cholesterol efflux.
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Affiliation(s)
- Ikechukwu C. Esobi
- Department of Food, Nutrition, and Packaging Sciences, Clemson University, Clemson, SC 29634, USA
| | - Olanrewaju Oladosu
- Department of Food, Nutrition, and Packaging Sciences, Clemson University, Clemson, SC 29634, USA
| | - Jing Echesabal-Chen
- Department of Food, Nutrition, and Packaging Sciences, Clemson University, Clemson, SC 29634, USA
| | - Rhonda R. Powell
- Clemson Light Imaging Facility, Clemson University, Clemson, SC 29634, USA
| | - Terri Bruce
- Clemson Light Imaging Facility, Clemson University, Clemson, SC 29634, USA
| | - Alexis Stamatikos
- Department of Food, Nutrition, and Packaging Sciences, Clemson University, Clemson, SC 29634, USA
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14
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Saenz-Pipaon G, Dichek DA. Targeting and delivery of microRNA-targeting antisense oligonucleotides in cardiovascular diseases. Atherosclerosis 2023; 374:44-54. [PMID: 36577600 PMCID: PMC10277317 DOI: 10.1016/j.atherosclerosis.2022.12.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 12/09/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022]
Abstract
Discovered three decades ago, microRNAs (miRNAs) are now recognized as key players in the pathophysiology of multiple human diseases, including those affecting the cardiovascular system. As such, miRNAs have emerged as promising therapeutic targets for preventing the onset and/or progression of several cardiovascular diseases. Anti-miRNA antisense oligonucleotides or "antagomirs" precisely block the activity of specific miRNAs and are therefore a promising therapeutic strategy to repress pathological miRNAs. In this review, we describe advancements in antisense oligonucleotide chemistry that have significantly improved efficacy and safety. Moreover, we summarize recent approaches for the targeted delivery of antagomirs to cardiovascular tissues, highlighting major advantages as well as limitations of viral (i.e., adenovirus, adeno-associated virus, and lentivirus) and non-viral (i.e., liposomes, extracellular vesicles, and polymer nanoparticles) delivery systems. We discuss recent preclinical studies that use targeted antagomir delivery systems to treat three major cardiovascular diseases (atherosclerosis, myocardial infarction, and cardiac hypertrophy, including hypertrophy caused by hypertension), highlighting therapeutic results and discussing challenges that limit clinical applicability.
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Affiliation(s)
- Goren Saenz-Pipaon
- Department of Medicine, University of Washington School of Medicine, Seattle, USA
| | - David A Dichek
- Department of Medicine, University of Washington School of Medicine, Seattle, USA.
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15
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Ahangari F, Price NL, Malik S, Chioccioli M, Bärnthaler T, Adams TS, Kim J, Pradeep SP, Ding S, Cosmos C, Rose KAS, McDonough JE, Aurelien NR, Ibarra G, Omote N, Schupp JC, DeIuliis G, Villalba Nunez JA, Sharma L, Ryu C, Dela Cruz CS, Liu X, Prasse A, Rosas I, Bahal R, Fernández-Hernando C, Kaminski N. microRNA-33 deficiency in macrophages enhances autophagy, improves mitochondrial homeostasis, and protects against lung fibrosis. JCI Insight 2023; 8:e158100. [PMID: 36626225 PMCID: PMC9977502 DOI: 10.1172/jci.insight.158100] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 01/05/2023] [Indexed: 01/11/2023] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disease. Recent findings have shown a marked metabolic reprogramming associated with changes in mitochondrial homeostasis and autophagy during pulmonary fibrosis. The microRNA-33 (miR-33) family of microRNAs (miRNAs) encoded within the introns of sterol regulatory element binding protein (SREBP) genes are master regulators of sterol and fatty acid (FA) metabolism. miR-33 controls macrophage immunometabolic response and enhances mitochondrial biogenesis, FA oxidation, and cholesterol efflux. Here, we show that miR-33 levels are increased in bronchoalveolar lavage (BAL) cells isolated from patients with IPF compared with healthy controls. We demonstrate that specific genetic ablation of miR-33 in macrophages protects against bleomycin-induced pulmonary fibrosis. The absence of miR-33 in macrophages improves mitochondrial homeostasis and increases autophagy while decreasing inflammatory response after bleomycin injury. Notably, pharmacological inhibition of miR-33 in macrophages via administration of anti-miR-33 peptide nucleic acids (PNA-33) attenuates fibrosis in different in vivo and ex vivo mice and human models of pulmonary fibrosis. These studies elucidate a major role of miR-33 in macrophages in the regulation of pulmonary fibrosis and uncover a potentially novel therapeutic approach to treat this disease.
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Affiliation(s)
- Farida Ahangari
- Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Nathan L. Price
- Vascular Biology and Therapeutics Program, Yale Center for Molecular and System Metabolism, Department of Comparative Medicine, and Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA
- Experimental Gerontology Section, Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, Maryland, USA
| | - Shipra Malik
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut, USA
| | - Maurizio Chioccioli
- Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Thomas Bärnthaler
- Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
| | - Taylor S. Adams
- Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Jooyoung Kim
- Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Sai Pallavi Pradeep
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut, USA
| | - Shuizi Ding
- Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Carlos Cosmos
- Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Kadi-Ann S. Rose
- Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - John E. McDonough
- Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Nachelle R. Aurelien
- Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
- Department of Internal Medicine, Weill Cornell Hospital Medicine, New York, New York, USA
| | - Gabriel Ibarra
- Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
- Life Span Medical Group, Department of Internal Medicine, Rhode Island Hospital, Providence, Rhode Island, USA
| | - Norihito Omote
- Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Jonas C. Schupp
- Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Giuseppe DeIuliis
- Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Julian A. Villalba Nunez
- Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Lokesh Sharma
- Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Changwan Ryu
- Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Charles S. Dela Cruz
- Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Xinran Liu
- Center for Cellular and Molecular Imaging (CCMI), Department of Cell Biology, Yale School of Medicine, New Haven, Connecticut, USA
| | - Antje Prasse
- Department of Pneumology, University of Hannover, Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany
| | - Ivan Rosas
- Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
- Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
| | - Raman Bahal
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut, USA
| | - Carlos Fernández-Hernando
- Vascular Biology and Therapeutics Program, Yale Center for Molecular and System Metabolism, Department of Comparative Medicine, and Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Naftali Kaminski
- Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
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16
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Stein RA, Thompson LM. Epigenetic changes induced by pathogenic Chlamydia spp. Pathog Dis 2023; 81:ftad034. [PMID: 38031337 DOI: 10.1093/femspd/ftad034] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 11/16/2023] [Accepted: 11/28/2023] [Indexed: 12/01/2023] Open
Abstract
Chlamydia trachomatis, C. pneumoniae, and C. psittaci, the three Chlamydia species known to cause human disease, have been collectively linked to several pathologies, including conjunctivitis, trachoma, respiratory disease, acute and chronic urogenital infections and their complications, and psittacosis. In vitro, animal, and human studies also established additional correlations, such as between C. pneumoniae and atherosclerosis and between C. trachomatis and ovarian cancer. As part of their survival and pathogenesis strategies as obligate intracellular bacteria, Chlamydia spp. modulate all three major types of epigenetic changes, which include deoxyribonucleic acid (DNA) methylation, histone post-translational modifications, and microRNA-mediated gene silencing. Some of these epigenetic changes may be implicated in key aspects of pathogenesis, such as the ability of the Chlamydia spp. to induce epithelial-to-mesenchymal transition, interfere with DNA damage repair, suppress cholesterol efflux from infected macrophages, act as a co-factor in human papillomavirus (HPV)-mediated cervical cancer, prevent apoptosis, and preserve the integrity of mitochondrial networks in infected host cells. A better understanding of the individual and collective contribution of epigenetic changes to pathogenesis will enhance our knowledge about the biology of Chlamydia spp. and facilitate the development of novel therapies and biomarkers. Pathogenic Chlamydia spp. contribute to epigenetically-mediated gene expression changes in host cells by multiple mechanisms.
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Affiliation(s)
- Richard A Stein
- NYU Tandon School of Engineering, Department of Chemical and Biomolecular Engineering, 6 MetroTech Center, Brooklyn, NY 11201, United States
| | - Lily M Thompson
- NYU Tandon School of Engineering, Department of Chemical and Biomolecular Engineering, 6 MetroTech Center, Brooklyn, NY 11201, United States
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17
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Khalifeh M, Santos RD, Oskuee RK, Badiee A, Aghaee-Bakhtiari SH, Sahebkar A. A novel regulatory facet for hypertriglyceridemia: The role of microRNAs in the regulation of triglyceride-rich lipoprotein biosynthesis. Prog Lipid Res 2023; 89:101197. [PMID: 36400247 DOI: 10.1016/j.plipres.2022.101197] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Revised: 11/04/2022] [Accepted: 11/08/2022] [Indexed: 11/17/2022]
Abstract
Atherosclerotic cardiovascular disease (ASCVD) is one of the major leading global causes of death. Genetic and epidemiological studies strongly support the causal association between triacylglycerol-rich lipoproteins (TAGRL) and atherogenesis, even in statin-treated patients. Recent genetic evidence has clarified that variants in several key genes implicated in TAGRL metabolism are strongly linked to the increased ASCVD risk. There are several triacylglycerol-lowering agents; however, new therapeutic options are in development, among which are miRNA-based therapeutic approaches. MicroRNAs (miRNAs) are small non-coding RNAs (18-25 nucleotides) that negatively modulate gene expression through translational repression or degradation of target mRNAs, thereby reducing the levels of functional genes. MiRNAs play a crucial role in the development of hypertriglyceridemia as several miRNAs are dysregulated in both synthesis and clearance of TAGRL particles. MiRNA-based therapies in ASCVD have not yet been applied in human trials but are attractive. This review provides a concise overview of current interventions for hypertriglyceridemia and the development of novel miRNA and siRNA-based drugs. We summarize the miRNAs involved in the regulation of key genes in the TAGRLs synthesis pathway, which has gained attention as a novel target for therapeutic applications in CVD.
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Affiliation(s)
- Masoumeh Khalifeh
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Raul D Santos
- Lipid Clinic Heart Institute (Incor), University of São Paulo, Medical School Hospital, São Paulo, Brazil
| | - Reza Kazemi Oskuee
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Badiee
- Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Biotechnology Research Centre, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; School of Medicine, The University of Western Australia, Perth, Australia; School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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18
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El Meouchy P, Wahoud M, Allam S, Chedid R, Karam W, Karam S. Hypertension Related to Obesity: Pathogenesis, Characteristics and Factors for Control. Int J Mol Sci 2022; 23:ijms232012305. [PMID: 36293177 PMCID: PMC9604511 DOI: 10.3390/ijms232012305] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 10/01/2022] [Accepted: 10/07/2022] [Indexed: 11/16/2022] Open
Abstract
The World Health Organization (WHO) refers to obesity as abnormal or excessive fat accumulation that presents a health risk. Obesity was first designated as a disease in 2012 and since then the cost and the burden of the disease have witnessed a worrisome increase. Obesity and hypertension are closely interrelated as abdominal obesity interferes with the endocrine and immune systems and carries a greater risk for insulin resistance, diabetes, hypertension, and cardiovascular disease. Many factors are at the interplay between obesity and hypertension. They include hemodynamic alterations, oxidative stress, renal injury, hyperinsulinemia, and insulin resistance, sleep apnea syndrome and the leptin-melanocortin pathway. Genetics, epigenetics, and mitochondrial factors also play a major role. The measurement of blood pressure in obese patients requires an adapted cuff and the search for other secondary causes is necessary at higher thresholds than the general population. Lifestyle modifications such as diet and exercise are often not enough to control obesity, and so far, bariatric surgery constitutes the most reliable method to achieve weight loss. Nonetheless, the emergence of new agents such as Semaglutide and Tirzepatide offers promising alternatives. Finally, several molecular pathways are actively being explored, and they should significantly extend the treatment options available.
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Affiliation(s)
- Paul El Meouchy
- Department of Internal Medicine, MedStar Health, Baltimore, MD 21218, USA
| | - Mohamad Wahoud
- Department of Internal Medicine, Tufts Medical Center, Boston, MA 02111, USA
| | - Sabine Allam
- Faculty of Medicine and Medical Sciences, University of Balamand, El Koura P.O. Box 100, Lebanon
| | - Roy Chedid
- College of Osteopathic Medicine, William Carey University, Hattiesburg, MS 39401, USA
| | - Wissam Karam
- Department of Internal Medicine, University of Kansas School of Medicine, Wichita, KS 67214, USA
| | - Sabine Karam
- Division of Nephrology and Hypertension, University of Minnesota, Minneapolis, MN 55414, USA
- Correspondence:
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19
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Rotllan N, Zhang X, Canfrán-Duque A, Goedeke L, Griñán R, Ramírez CM, Suárez Y, Fernández-Hernando C. Antagonism of miR-148a attenuates atherosclerosis progression in APOB TGApobec -/-Ldlr +/- mice: A brief report. Biomed Pharmacother 2022; 153:113419. [PMID: 36076541 PMCID: PMC11140622 DOI: 10.1016/j.biopha.2022.113419] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 07/12/2022] [Accepted: 07/13/2022] [Indexed: 11/25/2022] Open
Abstract
OBJECTIVE miR-148a-3p (miR-148a) is a hepatic and immune-enriched microRNA (miRNA) that regulates macrophage-related lipoprotein metabolism, cholesterol homeostasis, and inflammation. The contribution of miR-148a-3p to the progression of atherosclerosis is unknown. In this study, we determined whether miR-148a silencing mitigated atherogenesis in APOBTGApobec-/-Ldlr+/- mice. METHODS APOBTGApobec-/-Ldlr+/- mice were fed a typical Western-style diet for 22 weeks and injected with a nontargeting locked nucleic acid (LNA; LNA control) or miR-148a LNA (LNA 148a) for the last 10 weeks. At the end of the treatment, the mice were sacrificed, and circulating lipids, hepatic gene expression, and atherosclerotic lesions were analyzed. RESULTS Examination of atherosclerotic lesions revealed a significant reduction in plaque size, with marked remodeling of the lesions toward a more stable phenotype. Mechanistically, miR-148a levels influenced macrophage cholesterol efflux and the inflammatory response. Suppression of miR-148a in murine primary macrophages decreased mRNA levels of proinflammatory M1-like markers (Nos2, Il6, Cox2, and Tnf) and increased the expression of anti-inflammatory genes (Arg1, Retlna, and Mrc1). CONCLUSIONS Therapeutic silencing of miR148a mitigated the progression of atherosclerosis and promoted plaque stability. The antiatherogenic effect of miR-148a antisense therapy is likely mediated by the anti-inflammatory effects observed in macrophages treated with miR-148 LNA and independent of significant changes in circulating low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C).
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Affiliation(s)
- Noemi Rotllan
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA; Integrative Cell Signaling and Neurobiology of Metabolism Program, Department of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, CT, USA; Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain.
| | - Xinbo Zhang
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA; Integrative Cell Signaling and Neurobiology of Metabolism Program, Department of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
| | - Alberto Canfrán-Duque
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA; Integrative Cell Signaling and Neurobiology of Metabolism Program, Department of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
| | - Leigh Goedeke
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA; Integrative Cell Signaling and Neurobiology of Metabolism Program, Department of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
| | - Raquel Griñán
- Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain; Departament de Bioquímica i Biologia Molecular, Universitat Autònoma De Barcelona, Barcelona, Spain
| | - Cristina M Ramírez
- Integrative Cell Signaling and Neurobiology of Metabolism Program, Department of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, CT, USA; IMDEA Research Institute of Food and Health Sciences, Madrid, Spain
| | - Yajaira Suárez
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA; Integrative Cell Signaling and Neurobiology of Metabolism Program, Department of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
| | - Carlos Fernández-Hernando
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA; Integrative Cell Signaling and Neurobiology of Metabolism Program, Department of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
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20
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Jebari-Benslaiman S, Uribe KB, Benito-Vicente A, Galicia-Garcia U, Larrea-Sebal A, Santin I, Alloza I, Vandenbroeck K, Ostolaza H, Martín C. Boosting Cholesterol Efflux from Foam Cells by Sequential Administration of rHDL to Deliver MicroRNA and to Remove Cholesterol in a Triple-Cell 2D Atherosclerosis Model. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2022; 18:e2105915. [PMID: 35156292 DOI: 10.1002/smll.202105915] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 12/30/2021] [Indexed: 06/14/2023]
Abstract
Cardiovascular disease, the leading cause of mortality worldwide, is primarily caused by atherosclerosis, which is characterized by lipid and inflammatory cell accumulation in blood vessels and carotid intima thickening. Although disease management has improved significantly, new therapeutic strategies focused on accelerating atherosclerosis regression must be developed. Atherosclerosis models mimicking in vivo-like conditions provide essential information for research and new advances toward clinical application. New nanotechnology-based therapeutic opportunities have emerged with apoA-I nanoparticles (recombinant/reconstituted high-density lipoproteins, rHDL) as ideal carriers to deliver molecules and the discovery that microRNAs participate in atherosclerosis establishment and progression. Here, a therapeutic strategy to improve cholesterol efflux is developed based on a two-step administration of rHDL consisting of a first dose of antagomiR-33a-loaded rHDLs to induce adenosine triphosphate-binding cassette transporters A1 overexpression, followed by a second dose of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine rHDLs, which efficiently remove cholesterol from foam cells. A triple-cell 2D-atheroma plaque model reflecting the cellular complexity of atherosclerosis is used to improve efficiency of the nanoparticles in promoting cholesterol efflux. The results show that sequential administration of rHDL potentiates cholesterol efflux indicating that this approach may be used in vivo to more efficiently target atherosclerotic lesions and improve prognosis of the disease.
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Affiliation(s)
- Shifa Jebari-Benslaiman
- Biofisika Institute (UPV/EHU, CSIC) and Department of Biochemistry and Molecular Biology, University of the Basque Country UPV/EHU, Leioa, 48940, Spain
| | - Kepa B Uribe
- Center for Cooperative Research in Biomaterials (CIC biomaGUNE), Basque Research and Technology Alliance (BRTA), San Sebastián, 20014, Spain
| | - Asier Benito-Vicente
- Biofisika Institute (UPV/EHU, CSIC) and Department of Biochemistry and Molecular Biology, University of the Basque Country UPV/EHU, Leioa, 48940, Spain
| | - Unai Galicia-Garcia
- Fundación Biofisika Bizkaia and Biofisika Institute (UPV/EHU, CSIC), Leioa, 48940, Spain
| | - Asier Larrea-Sebal
- Fundación Biofisika Bizkaia and Biofisika Institute (UPV/EHU, CSIC), Leioa, 48940, Spain
| | - Izortze Santin
- Department of Biochemistry and Molecular biology, University of the Basque Country UPV/EHU, Leioa, 48940, Spain
- Biocruces Bizkaia Health Research Institute, Barakaldo, 48903, Spain
- CIBER (Centro de Investigación Biomédica en Red) de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Spain
| | - Iraide Alloza
- Biocruces Bizkaia Health Research Institute, Barakaldo, 48903, Spain
| | - Koen Vandenbroeck
- Biocruces Bizkaia Health Research Institute, Barakaldo, 48903, Spain
| | - Helena Ostolaza
- Biofisika Institute (UPV/EHU, CSIC) and Department of Biochemistry and Molecular Biology, University of the Basque Country UPV/EHU, Leioa, 48940, Spain
| | - César Martín
- Biofisika Institute (UPV/EHU, CSIC) and Department of Biochemistry and Molecular Biology, University of the Basque Country UPV/EHU, Leioa, 48940, Spain
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21
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Jebari-Benslaiman S, Galicia-García U, Larrea-Sebal A, Olaetxea JR, Alloza I, Vandenbroeck K, Benito-Vicente A, Martín C. Pathophysiology of Atherosclerosis. Int J Mol Sci 2022; 23:ijms23063346. [PMID: 35328769 PMCID: PMC8954705 DOI: 10.3390/ijms23063346] [Citation(s) in RCA: 393] [Impact Index Per Article: 131.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 03/12/2022] [Accepted: 03/18/2022] [Indexed: 11/26/2022] Open
Abstract
Atherosclerosis is the main risk factor for cardiovascular disease (CVD), which is the leading cause of mortality worldwide. Atherosclerosis is initiated by endothelium activation and, followed by a cascade of events (accumulation of lipids, fibrous elements, and calcification), triggers the vessel narrowing and activation of inflammatory pathways. The resultant atheroma plaque, along with these processes, results in cardiovascular complications. This review focuses on the different stages of atherosclerosis development, ranging from endothelial dysfunction to plaque rupture. In addition, the post-transcriptional regulation and modulation of atheroma plaque by microRNAs and lncRNAs, the role of microbiota, and the importance of sex as a crucial risk factor in atherosclerosis are covered here in order to provide a global view of the disease.
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Affiliation(s)
- Shifa Jebari-Benslaiman
- Department of Biochemistry and Molecular Biology, Universidad del País Vasco UPV/EHU, 48940 Leioa, Bizkaia, Spain; (S.J.-B.); (I.A.); (K.V.)
- Biofisika Institute (UPV/EHU, CSIC), Barrio Sarriena s/n., 48940 Leioa, Bizkaia, Spain; (U.G.-G.); (A.L.-S.)
| | - Unai Galicia-García
- Biofisika Institute (UPV/EHU, CSIC), Barrio Sarriena s/n., 48940 Leioa, Bizkaia, Spain; (U.G.-G.); (A.L.-S.)
- Fundación Biofisika Bizkaia, Barrio Sarriena s/n., 48940 Leioa, Bizkaia, Spain
| | - Asier Larrea-Sebal
- Biofisika Institute (UPV/EHU, CSIC), Barrio Sarriena s/n., 48940 Leioa, Bizkaia, Spain; (U.G.-G.); (A.L.-S.)
- Fundación Biofisika Bizkaia, Barrio Sarriena s/n., 48940 Leioa, Bizkaia, Spain
| | | | - Iraide Alloza
- Department of Biochemistry and Molecular Biology, Universidad del País Vasco UPV/EHU, 48940 Leioa, Bizkaia, Spain; (S.J.-B.); (I.A.); (K.V.)
- Inflammation & Biomarkers Group, Biocruces Bizkaia Health Research Institute, 48903 Barakaldo, Bizkaia, Spain
| | - Koen Vandenbroeck
- Department of Biochemistry and Molecular Biology, Universidad del País Vasco UPV/EHU, 48940 Leioa, Bizkaia, Spain; (S.J.-B.); (I.A.); (K.V.)
- Inflammation & Biomarkers Group, Biocruces Bizkaia Health Research Institute, 48903 Barakaldo, Bizkaia, Spain
- Ikerbasque, Basque Foundation for Science, 48013 Bilbao, Bizkaia, Spain
| | - Asier Benito-Vicente
- Department of Biochemistry and Molecular Biology, Universidad del País Vasco UPV/EHU, 48940 Leioa, Bizkaia, Spain; (S.J.-B.); (I.A.); (K.V.)
- Biofisika Institute (UPV/EHU, CSIC), Barrio Sarriena s/n., 48940 Leioa, Bizkaia, Spain; (U.G.-G.); (A.L.-S.)
- Correspondence: (A.B.-V.); (C.M.); Tel.: +34-946-01-2741 (C.M.)
| | - César Martín
- Department of Biochemistry and Molecular Biology, Universidad del País Vasco UPV/EHU, 48940 Leioa, Bizkaia, Spain; (S.J.-B.); (I.A.); (K.V.)
- Biofisika Institute (UPV/EHU, CSIC), Barrio Sarriena s/n., 48940 Leioa, Bizkaia, Spain; (U.G.-G.); (A.L.-S.)
- Correspondence: (A.B.-V.); (C.M.); Tel.: +34-946-01-2741 (C.M.)
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22
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Dorairaj V, Sulaiman SA, Abu N, Abdul Murad NA. Nonalcoholic Fatty Liver Disease (NAFLD): Pathogenesis and Noninvasive Diagnosis. Biomedicines 2021; 10:15. [PMID: 35052690 PMCID: PMC8773432 DOI: 10.3390/biomedicines10010015] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/20/2021] [Accepted: 12/20/2021] [Indexed: 12/14/2022] Open
Abstract
The global prevalence of nonalcoholic fatty liver disease (NAFLD) or metabolic associated fatty liver disease (MAFLD), as it is now known, has gradually increased. NAFLD is a disease with a spectrum of stages ranging from simple fatty liver (steatosis) to a severe form of steatosis, nonalcoholic steatohepatitis (NASH), which could progress to irreversible liver injury (fibrosis) and organ failure, and in some cases hepatocellular carcinoma (HCC). Although a liver biopsy remains the gold standard for accurate detection of this condition, it is unsuitable for clinical screening due to a higher risk of death. There is thus an increased need to find alternative techniques or tools for accurate diagnosis. Early detection for NASH matters for patients because NASH is the marker for severe disease progression. This review summarizes the current noninvasive tools for NAFLD diagnosis and their performance. We also discussed potential and newer alternative tools for diagnosing NAFLD.
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Affiliation(s)
| | - Siti Aishah Sulaiman
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia (UKM), Kuala Lumpur 56000, Malaysia; (V.D.); (N.A.); (N.A.A.M.)
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23
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He XY, Ou CL. Clinical significance of serum miR-129-5p in patients with diabetes mellitus presenting macrovascular complications. World J Diabetes 2021; 12:1282-1291. [PMID: 34512893 PMCID: PMC8394230 DOI: 10.4239/wjd.v12.i8.1282] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 05/24/2021] [Accepted: 07/06/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Diabetic macrovascular complications (DMCs) are the most common complications encountered during the course of diabetes mellitus (DM) with extremely high mortality rates. Therefore, there is an urgent need to identify specific and sensitive biomarkers for the early diagnosis of DMCs. AIM To investigate the expression and significance of serum miR-129-5p in patients with DM and macrovascular complications. METHODS Serum samples were collected from 36 healthy controls, 58 patients with DM presenting no macrovascular complications, and 62 patients with DMCs. The expression of miR-129-5p was detected using quantitative real-time polymerase chain reaction. Pearson's correlation assay was performed to analyze the correlation between serum miR-129-5p levels and clinical indicators. Receiver operator characteristic (ROC) analysis was conducted to analyze the diagnostic value of serum miR-129-5p in patients with DM or DMCs. RESULTS There was a 4.378-fold and 7.369-fold increase in serum miR-129-5p expression in the DM (5.346 ± 0.405) and DMCs (8.998 ± 0.631) groups, respectively (P < 0.001), compared with the control group (1.221±0.090). In addition, the expression of serum miR-129-5p in patients with DMCs was higher than that in patients with DM, revealing a 1.683-fold increase (P < 0.001). Additionally, serum miR-129-5p expression significantly correlated with smoking history, disease duration, and glycated hemoglobin (HbA1c) in patients with DMCs (P < 0.001). The area under the ROC curve (AUC) of miR-129-5p as a serum marker was 0.964 (95% confidence interval [CI]: 0.930-0.997, P < 0.001) in distinguishing between patients with DM and healthy controls, whereas the AUC of miR-129-5p as a serum marker was 0.979 (95%CI: 0.959-0.999, P < 0.001) in distinguishing between patients with DMCs and healthy controls. CONCLUSION Elevated serum miR-129-5p expression levels correlate with the development of DMCs and can be utilized as a novel early diagnostic biomarker for DM combined with macrovascular complications.
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Affiliation(s)
- Xiao-Yun He
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Department of Endocrinology, Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
| | - Chun-Lin Ou
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
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24
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Price NL, Goedeke L, Suárez Y, Fernández-Hernando C. miR-33 in cardiometabolic diseases: lessons learned from novel animal models and approaches. EMBO Mol Med 2021; 13:e12606. [PMID: 33938628 PMCID: PMC8103095 DOI: 10.15252/emmm.202012606] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 01/30/2021] [Accepted: 02/03/2021] [Indexed: 12/28/2022] Open
Abstract
miRNAs have emerged as critical regulators of nearly all biologic processes and important therapeutic targets for numerous diseases. However, despite the tremendous progress that has been made in this field, many misconceptions remain among much of the broader scientific community about the manner in which miRNAs function. In this review, we focus on miR‐33, one of the most extensively studied miRNAs, as an example, to highlight many of the advances that have been made in the miRNA field and the hurdles that must be cleared to promote the development of miRNA‐based therapies. We discuss how the generation of novel animal models and newly developed experimental techniques helped to elucidate the specialized roles of miR‐33 within different tissues and begin to define the specific mechanisms by which miR‐33 contributes to cardiometabolic diseases including obesity and atherosclerosis. This review will summarize what is known about miR‐33 and highlight common obstacles in the miRNA field and then describe recent advances and approaches that have allowed researchers to provide a more complete picture of the specific functions of this miRNA.
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Affiliation(s)
- Nathan L Price
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA.,Department of Comparative Medicine, Integrative Cell Signaling and Neurobiology of Metabolism Program, Yale University School of Medicine, New Haven, CT, USA
| | - Leigh Goedeke
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Yajaira Suárez
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA.,Department of Comparative Medicine, Integrative Cell Signaling and Neurobiology of Metabolism Program, Yale University School of Medicine, New Haven, CT, USA.,Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
| | - Carlos Fernández-Hernando
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA.,Department of Comparative Medicine, Integrative Cell Signaling and Neurobiology of Metabolism Program, 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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