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Wang X, Geng S, Dai L, Niu Y, Chen J, Dong C, Liu R, Shi Y, Zhang J, Zhao N, Gao Z, Gao S, Yang X. Unc5b prevents macrophage-derived foam cell migration and promotes atherosclerotic development via the P53-cuproptosis signaling pathway. Life Sci 2025; 361:123334. [PMID: 39722317 DOI: 10.1016/j.lfs.2024.123334] [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: 08/15/2024] [Revised: 10/03/2024] [Accepted: 12/19/2024] [Indexed: 12/28/2024]
Abstract
BACKGROUND Atherosclerosis involves the buildup of macrophage-derived foam cells in the arterial intima. Facilitating the egress of these cells from plaques can significantly slow disease progression. The transmembrane receptor Unc5b, a vascular-specific axon guidance receptor, is upregulated in foam cells, and inhibits their migration from the plaques. However, the mechanisms underlying Unc5b's regulation of foam cell production and retention within plaques, along with its downstream signaling pathways, remain insufficiently understood. METHODS We employed both a foam cell model and an ApoE-deficient mouse model of atherosclerosis to evaluate these effects. Western blotting, RT-PCR, wound healing assays, and immunofluorescence staining were performed to explore the role of Unc5b in foam cell migration. RESULTS Unc5b played a role in advancing atherosclerosis by regulating the P53-cuproptosis pathway, thereby inhibiting the migration of foam cells. Stimulation of Raw264.7 cells with oxidized low-density lipoprotein (ox-LDL) resulted in increased cuproptosis and inflammation, impacting migration regulation. Macrophage-derived foam cell migration was prevented by Unc5b via the P53-cuproptosis signaling pathway. Notably, PFT-α (a P53 inhibitor) and VI (a Cu2+ chelator) counteracted the inhibitory effect of ox-LDL on migration. Similarly, upregulation of cuproptosis-related proteins was observed within the aortic sinus plaques of ApoE-/- mice fed a hyperlipidemic diet. Importantly, the progression of atherosclerosis induced by a hyperlipidemic diet can be effectively reversed by PFT-α and VI. CONCLUSION These findings underscore Unc5b's role in promoting inflammation, inhibiting macrophage migration, and promoting atherosclerotic development via the P53-cuproptosis signaling pathway.
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Affiliation(s)
- Xiaomeng Wang
- Graduate School of Inner Mongolia Medical University, Inner Mongolia Medical University, Hohhot 010110, PR China; College of Basic Medicine, Inner Mongolia Medical University, Hohhot 010110, PR China
| | - Shijia Geng
- College of Basic Medicine, Inner Mongolia Medical University, Hohhot 010110, PR China; Medical Experiments Center, Inner Mongolia Medical University, Hohhot 010110, PR China
| | - Lina Dai
- College of Basic Medicine, Inner Mongolia Medical University, Hohhot 010110, PR China; Medical Experiments Center, Inner Mongolia Medical University, Hohhot 010110, PR China
| | - Yan Niu
- Medical Experiments Center, Inner Mongolia Medical University, Hohhot 010110, PR China
| | - Jie Chen
- College of Basic Medicine, Inner Mongolia Medical University, Hohhot 010110, PR China; Medical Experiments Center, Inner Mongolia Medical University, Hohhot 010110, PR China
| | - Chongyang Dong
- Medical Experiments Center, Inner Mongolia Medical University, Hohhot 010110, PR China; College of Traditional Chinese Medicine, Inner Mongolia Medical University, Hohhot 010110, PR China
| | - Rujin Liu
- Graduate School of Inner Mongolia Medical University, Inner Mongolia Medical University, Hohhot 010110, PR China; College of Basic Medicine, Inner Mongolia Medical University, Hohhot 010110, PR China
| | - Yuanjia Shi
- Graduate School of Inner Mongolia Medical University, Inner Mongolia Medical University, Hohhot 010110, PR China; College of Basic Medicine, Inner Mongolia Medical University, Hohhot 010110, PR China
| | - Jing Zhang
- Graduate School of Inner Mongolia Medical University, Inner Mongolia Medical University, Hohhot 010110, PR China; College of Basic Medicine, Inner Mongolia Medical University, Hohhot 010110, PR China
| | - Ningxia Zhao
- Graduate School of Inner Mongolia Medical University, Inner Mongolia Medical University, Hohhot 010110, PR China; College of Basic Medicine, Inner Mongolia Medical University, Hohhot 010110, PR China
| | - Zhanfeng Gao
- The Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010110, PR China
| | - Shang Gao
- College of Basic Medicine, Inner Mongolia Medical University, Hohhot 010110, PR China; Medical Experiments Center, Inner Mongolia Medical University, Hohhot 010110, PR China.
| | - Xi Yang
- College of Basic Medicine, Inner Mongolia Medical University, Hohhot 010110, PR China; Medical Experiments Center, Inner Mongolia Medical University, Hohhot 010110, PR China.
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Chong L, Dushaj N, Rakoubian A, Yarbro J, Kobayashi S, Liang Q. Unraveling the Roles of HIF-1, HO-1, GLUT-1 and GLUT-4 in Myocardial Protection. INTERNATIONAL JOURNAL OF DRUG DISCOVERY AND PHARMACOLOGY 2024; 3:100016. [PMID: 40376262 PMCID: PMC12080592 DOI: 10.53941/ijddp.2024.100016] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 05/18/2025]
Abstract
Cardiomyocytes are highly dependent on oxygen for optimal function. Disruption of oxygen availability, as in the case of ischemic heart disease, can significantly impair heart function. Moreover, comorbidities like diabetes, hyperlipidemia, and hypertension can exacerbate ischemic cardiac injury. However, cardiomyocytes possess inherent protective mechanisms that can be activated to enhance myocardial survival under such conditions. Understanding the functions and regulatory mechanisms of these cardioprotective genes is crucial for advancing our knowledge of cardiovascular health and for developing therapeutic strategies. This review examines the intricate mechanisms of cardioprotection, with a focus on key genes and proteins, including hypoxia-inducible factor-1 (HIF-1), heme oxygenase-1 (HO-1), glucose transporter 1 (GLUT-1), and GLUT-4. In addition, the review explores the roles and regulation of these factors in the heart under ischemic stress, shedding light on their relevance in conditions like diabetes, hypertension, and hyperlipidemia/atherosclerosis. Moreover, it highlights the complex interplay among their mechanisms and suggests opportunities for developing targeted therapiesfor the treatment of ischemic heart disease, hypertension, and hyperlipidemia.
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Affiliation(s)
- Lionel Chong
- Department of Biomedical Sciences, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, NY 11568-8000, USA
| | - Nicholas Dushaj
- Department of Biomedical Sciences, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, NY 11568-8000, USA
| | - Ani Rakoubian
- Department of Biomedical Sciences, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, NY 11568-8000, USA
| | - Johnathan Yarbro
- Department of Biomedical Sciences, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, NY 11568-8000, USA
| | - Satoru Kobayashi
- Department of Biomedical Sciences, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, NY 11568-8000, USA
| | - Qiangrong Liang
- Department of Biomedical Sciences, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, NY 11568-8000, USA
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Fleetwood AJ, Noonan J, La Gruta N, Kallies A, Murphy AJ. Immunometabolism in atherosclerotic disorders. NATURE CARDIOVASCULAR RESEARCH 2024; 3:637-650. [PMID: 39196223 DOI: 10.1038/s44161-024-00473-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 04/11/2024] [Indexed: 08/29/2024]
Abstract
Cardiovascular diseases (CVDs), including atherosclerosis, myocardial infarction and heart failure, are the leading causes of morbidity and mortality worldwide. Emerging evidence suggests a crucial role for immune cell dysfunction and inflammation in the progression of this complex set of diseases. Recent advances demonstrate that immune cells, tightly linked to CVD pathogenesis, are sensitive to environmental signals and respond by engaging immunometabolic networks that shape their behavior. Inflammatory cues and altered nutrient availability within atherosclerotic plaques or following ischemia synergize to elicit metabolic shifts in immune cells that influence the course of disease pathology. Understanding these metabolic adaptations and how they contribute to cellular dysfunction may reveal novel therapeutic approaches for the treatment of CVD. Here we provide a comprehensive summary of the metabolic reprogramming that occurs in immune cells and their progenitors during CVD, offering insights into the potential therapeutic interventions to mitigate disease progression.
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Affiliation(s)
- Andrew J Fleetwood
- Division of Immunometabolism, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.
| | - Jonathan Noonan
- Division of Immunometabolism, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Nicole La Gruta
- Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| | - Axel Kallies
- The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia
| | - Andrew J Murphy
- Division of Immunometabolism, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.
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4
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An X, Mao L, Wang Y, Xu Q, Liu X, Zhang S, Qiao Z, Li B, Li F, Kuang Z, Wan N, Liang X, Duan Q, Feng Z, Yang X, Liu S, Nevo E, Liu J, Storz JF, Li K. Genomic structural variation is associated with hypoxia adaptation in high-altitude zokors. Nat Ecol Evol 2024; 8:339-351. [PMID: 38195998 DOI: 10.1038/s41559-023-02275-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 11/20/2023] [Indexed: 01/11/2024]
Abstract
Zokors, an Asiatic group of subterranean rodents, originated in lowlands and colonized high-elevational zones following the uplift of the Qinghai-Tibet plateau about 3.6 million years ago. Zokors live at high elevation in subterranean burrows and experience hypobaric hypoxia, including both hypoxia (low oxygen concentration) and hypercapnia (elevated partial pressure of CO2). Here we report a genomic analysis of six zokor species (genus Eospalax) with different elevational ranges to identify structural variants (deletions and inversions) that may have contributed to high-elevation adaptation. Based on an assembly of a chromosome-level genome of the high-elevation species, Eospalax baileyi, we identified 18 large inversions that distinguished this species from congeners native to lower elevations. Small-scale structural variants in the introns of EGLN1, HIF1A, HSF1 and SFTPD of E. baileyi were associated with the upregulated expression of those genes. A rearrangement on chromosome 1 was associated with altered chromatin accessibility, leading to modified gene expression profiles of key genes involved in the physiological response to hypoxia. Multigene families that underwent copy-number expansions in E. baileyi were enriched for autophagy, HIF1 signalling and immune response. E. baileyi show a significantly larger lung mass than those of other Eospalax species. These findings highlight the key role of structural variants underlying hypoxia adaptation of high-elevation species in Eospalax.
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Affiliation(s)
- Xuan An
- State Key Laboratory of Herbage Improvement and Grassland Agro-ecosystems, College of Ecology, Lanzhou University, Lanzhou, China
| | - Leyan Mao
- State Key Laboratory of Herbage Improvement and Grassland Agro-ecosystems, College of Ecology, Lanzhou University, Lanzhou, China
| | - Yinjia Wang
- State Key Laboratory of Herbage Improvement and Grassland Agro-ecosystems, College of Ecology, Lanzhou University, Lanzhou, China
| | - Qinqin Xu
- Department of Medical Oncology, Qinghai Provincial People's Hospital, Xining, China
| | - Xi Liu
- State Key Laboratory of Herbage Improvement and Grassland Agro-ecosystems, College of Ecology, Lanzhou University, Lanzhou, China
| | - Shangzhe Zhang
- State Key Laboratory of Herbage Improvement and Grassland Agro-ecosystems, College of Ecology, Lanzhou University, Lanzhou, China
| | - Zhenglei Qiao
- College of Life Sciences and Technology, Mudanjiang Normal University, Mudanjiang, China
| | - Bowen Li
- State Key Laboratory of Herbage Improvement and Grassland Agro-ecosystems, College of Ecology, Lanzhou University, Lanzhou, China
| | - Fang Li
- College of Life Sciences and Technology, Mudanjiang Normal University, Mudanjiang, China
| | - Zhuoran Kuang
- State Key Laboratory of Herbage Improvement and Grassland Agro-ecosystems, College of Ecology, Lanzhou University, Lanzhou, China
| | - Na Wan
- State Key Laboratory of Herbage Improvement and Grassland Agro-ecosystems, College of Ecology, Lanzhou University, Lanzhou, China
| | - Xiaolong Liang
- State Key Laboratory of Herbage Improvement and Grassland Agro-ecosystems, College of Ecology, Lanzhou University, Lanzhou, China
| | - Qijiao Duan
- State Key Laboratory of Herbage Improvement and Grassland Agro-ecosystems, College of Ecology, Lanzhou University, Lanzhou, China
| | - Zhilong Feng
- State Key Laboratory of Herbage Improvement and Grassland Agro-ecosystems, College of Ecology, Lanzhou University, Lanzhou, China
| | - Xiaojie Yang
- State Key Laboratory of Herbage Improvement and Grassland Agro-ecosystems, College of Ecology, Lanzhou University, Lanzhou, China
| | - Sanyuan Liu
- State Key Laboratory of Herbage Improvement and Grassland Agro-ecosystems, College of Ecology, Lanzhou University, Lanzhou, China
| | - Eviatar Nevo
- Institute of Evolution, University of Haifa, Haifa, Israel
| | - Jianquan Liu
- State Key Laboratory of Herbage Improvement and Grassland Agro-ecosystems, College of Ecology, Lanzhou University, Lanzhou, China.
| | - Jay F Storz
- School of Biological Sciences, University of Nebraska, Lincoln, NE, USA.
| | - Kexin Li
- State Key Laboratory of Herbage Improvement and Grassland Agro-ecosystems, College of Ecology, Lanzhou University, Lanzhou, China.
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Fuenzalida B, Yañez MJ, Mueller M, Mistry HD, Leiva A, Albrecht C. Evidence for hypoxia-induced dysregulated cholesterol homeostasis in preeclampsia: Insights into the mechanisms from human placental cells and tissues. FASEB J 2024; 38:e23431. [PMID: 38265294 PMCID: PMC10953329 DOI: 10.1096/fj.202301708rr] [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: 08/24/2023] [Revised: 12/21/2023] [Accepted: 01/04/2024] [Indexed: 01/25/2024]
Abstract
Preeclampsia (PE) poses a considerable risk to the long-term cardiovascular health of both mothers and their offspring due to a hypoxic environment in the placenta leading to reduced fetal oxygen supply. Cholesterol is vital for fetal development by influencing placental function. Recent findings suggest an association between hypoxia, disturbed cholesterol homeostasis, and PE. This study investigates the influence of hypoxia on placental cholesterol homeostasis. Using primary human trophoblast cells and placentae from women with PE, various aspects of cholesterol homeostasis were examined under hypoxic and hypoxia/reoxygenation (H/R) conditions. Under hypoxia and H/R, intracellular total and non-esterified cholesterol levels were significantly increased. This coincided with an upregulation of HMG-CoA-reductase and HMG-CoA-synthase (key genes regulating cholesterol biosynthesis), and a decrease in acetyl-CoA-acetyltransferase-1 (ACAT1), which mediates cholesterol esterification. Hypoxia and H/R also increased the intracellular levels of reactive oxygen species and elevated the expression of hypoxia-inducible factor (HIF)-2α and sterol-regulatory-element-binding-protein (SREBP) transcription factors. Additionally, exposure of trophoblasts to hypoxia and H/R resulted in enhanced cholesterol efflux to maternal and fetal serum. This was accompanied by an increased expression of proteins involved in cholesterol transport such as the scavenger receptor class B type I (SR-BI) and the ATP-binding cassette transporter G1 (ABCG1). Despite these metabolic alterations, mitogen-activated-protein-kinase (MAPK) signaling, a key regulator of cholesterol homeostasis, was largely unaffected. Our findings indicate dysregulation of cholesterol homeostasis at multiple metabolic points in both the trophoblast hypoxia model and placentae from women with PE. The increased cholesterol efflux and intracellular accumulation of non-esterified cholesterol may have critical implications for both the mother and the fetus during pregnancy, potentially contributing to an elevated cardiovascular risk later in life.
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Affiliation(s)
- Barbara Fuenzalida
- Institute of Biochemistry and Molecular Medicine, Faculty of MedicineUniversity of BernBernSwitzerland
| | - Maria Jose Yañez
- School of Medical Technology, Faculty of Medicine and ScienceUniversidad San SebastiánSantiagoChile
| | - Martin Mueller
- Division of Gynecology and ObstetricsLindenhofgruppeBernSwitzerland
- Department for BioMedical ResearchUniversity of BernBernSwitzerland
| | - Hiten D. Mistry
- Department of Women and Children's HealthSchool of Life Course and Population Health Sciences, King's College LondonLondonUK
| | - Andrea Leiva
- School of Medical Technology, Faculty of Medicine and ScienceUniversidad San SebastiánSantiagoChile
| | - Christiane Albrecht
- Institute of Biochemistry and Molecular Medicine, Faculty of MedicineUniversity of BernBernSwitzerland
- Swiss National Center of Competence in Research, NCCR TransCureUniversity of BernBernSwitzerland
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6
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Hang L, Zhang Y, Zhang Z, Jiang H, Xia L. Metabolism Serves as a Bridge Between Cardiomyocytes and Immune Cells in Cardiovascular Diseases. Cardiovasc Drugs Ther 2024:10.1007/s10557-024-07545-5. [PMID: 38236378 DOI: 10.1007/s10557-024-07545-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/06/2023] [Indexed: 01/19/2024]
Abstract
Metabolic disorders of cardiomyocytes play an important role in the progression of various cardiovascular diseases. Metabolic reprogramming can provide ATP to cardiomyocytes and protect them during diseases, but this transformation also leads to adverse consequences such as oxidative stress, mitochondrial dysfunction, and eventually aggravates myocardial injury. Moreover, abnormal accumulation of metabolites induced by metabolic reprogramming of cardiomyocytes alters the cardiac microenvironment and affects the metabolism of immune cells. Immunometabolism, as a research hotspot, is involved in regulating the phenotype and function of immune cells. After myocardial injury, both cardiac resident immune cells and heart-infiltrating immune cells significantly contribute to the inflammation, repair and remodeling of the heart. In addition, metabolites generated by the metabolic reprogramming of immune cells can further affect the microenvironment, thereby affecting the function of cardiomyocytes and other immune cells. Therefore, metabolic reprogramming and abnormal metabolite levels may serve as a bridge between cardiomyocytes and immune cells, leading to the development of cardiovascular diseases. Herein, we summarize the metabolic relationship between cardiomyocytes and immune cells in cardiovascular diseases, and the effect on cardiac injury, which could be therapeutic strategy for cardiovascular diseases, especially in drug research.
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Affiliation(s)
- Lixiao Hang
- Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, No. 438 Jiefang Road, Zhenjiang, 212001, China
- International Genome Center, Jiangsu University, Zhenjiang, 212013, China
| | - Ying Zhang
- Department of Biochemistry and Molecular Biology, School of Medicine, Jiangsu University, Zhenjiang, 212013, China
| | - Zheng Zhang
- International Genome Center, Jiangsu University, Zhenjiang, 212013, China
| | - Haiqiang Jiang
- Department of Laboratory Medicine, Jiangyin Hospital of Traditional Chinese Medicine, No.130 Renmin Middle Road, Wuxi, 214400, Jiangyin, China.
| | - Lin Xia
- Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, No. 438 Jiefang Road, Zhenjiang, 212001, China.
- Institute of Hematological Disease, Jiangsu University, Zhenjiang, 212001, China.
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7
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Zhao Y, Xiong W, Li C, Zhao R, Lu H, Song S, Zhou Y, Hu Y, Shi B, Ge J. Hypoxia-induced signaling in the cardiovascular system: pathogenesis and therapeutic targets. Signal Transduct Target Ther 2023; 8:431. [PMID: 37981648 PMCID: PMC10658171 DOI: 10.1038/s41392-023-01652-9] [Citation(s) in RCA: 73] [Impact Index Per Article: 36.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 09/10/2023] [Accepted: 09/13/2023] [Indexed: 11/21/2023] Open
Abstract
Hypoxia, characterized by reduced oxygen concentration, is a significant stressor that affects the survival of aerobic species and plays a prominent role in cardiovascular diseases. From the research history and milestone events related to hypoxia in cardiovascular development and diseases, The "hypoxia-inducible factors (HIFs) switch" can be observed from both temporal and spatial perspectives, encompassing the occurrence and progression of hypoxia (gradual decline in oxygen concentration), the acute and chronic manifestations of hypoxia, and the geographical characteristics of hypoxia (natural selection at high altitudes). Furthermore, hypoxia signaling pathways are associated with natural rhythms, such as diurnal and hibernation processes. In addition to innate factors and natural selection, it has been found that epigenetics, as a postnatal factor, profoundly influences the hypoxic response and progression within the cardiovascular system. Within this intricate process, interactions between different tissues and organs within the cardiovascular system and other systems in the context of hypoxia signaling pathways have been established. Thus, it is the time to summarize and to construct a multi-level regulatory framework of hypoxia signaling and mechanisms in cardiovascular diseases for developing more therapeutic targets and make reasonable advancements in clinical research, including FDA-approved drugs and ongoing clinical trials, to guide future clinical practice in the field of hypoxia signaling in cardiovascular diseases.
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Affiliation(s)
- Yongchao Zhao
- Department of Cardiology, Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, China
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, 200032, China
| | - Weidong Xiong
- Department of Cardiology, Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, China
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, 200032, China
- Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai, 200032, China
- Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, 200032, China
| | - Chaofu Li
- Department of Cardiology, Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, China
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, 200032, China
| | - Ranzun Zhao
- Department of Cardiology, Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, China
| | - Hao Lu
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, 200032, China
- National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China
- Shanghai Clinical Research Center for Interventional Medicine, Shanghai, 200032, China
| | - Shuai Song
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, 200032, China
- National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China
- Shanghai Clinical Research Center for Interventional Medicine, Shanghai, 200032, China
| | - You Zhou
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, 200032, China
- National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China
- Shanghai Clinical Research Center for Interventional Medicine, Shanghai, 200032, China
| | - Yiqing Hu
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, 200032, China.
| | - Bei Shi
- Department of Cardiology, Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, China.
| | - Junbo Ge
- Department of Cardiology, Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, China.
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, 200032, China.
- Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai, 200032, China.
- Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, 200032, China.
- National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China.
- Shanghai Clinical Research Center for Interventional Medicine, Shanghai, 200032, China.
- Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
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8
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Bolshette N, Ezagouri S, Dandavate V, Karavaeva I, Golik M, Wang H, Espenshade PJ, Osborne TF, Han X, Asher G. Carbon dioxide regulates cholesterol levels through SREBP2. PLoS Biol 2023; 21:e3002367. [PMID: 37967106 PMCID: PMC10651039 DOI: 10.1371/journal.pbio.3002367] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 10/06/2023] [Indexed: 11/17/2023] Open
Abstract
In mammals, O2 and CO2 levels are tightly regulated and are altered under various pathological conditions. While the molecular mechanisms that participate in O2 sensing are well characterized, little is known regarding the signaling pathways that participate in CO2 signaling and adaptation. Here, we show that CO2 levels control a distinct cellular transcriptional response that differs from mere pH changes. Unexpectedly, we discovered that CO2 regulates the expression of cholesterogenic genes in a SREBP2-dependent manner and modulates cellular cholesterol accumulation. Molecular dissection of the underlying mechanism suggests that CO2 triggers SREBP2 activation through changes in endoplasmic reticulum (ER) membrane cholesterol levels. Collectively, we propose that SREBP2 participates in CO2 signaling and that cellular cholesterol levels can be modulated by CO2 through SREBP2.
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Affiliation(s)
- Nityanand Bolshette
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel
| | - Saar Ezagouri
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel
| | - Vaishnavi Dandavate
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel
| | - Iuliia Karavaeva
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel
| | - Marina Golik
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel
| | - Hu Wang
- The Sam & Ann Barshop Institute for Longevity & Aging Studies, University of Texas Health Science Center, San Antonio, Texas, United States of America
| | - Peter J. Espenshade
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Timothy F. Osborne
- Institute for Fundamental Biomedical Research, Johns Hopkins All Children’s Hospital, and Medicine in the Division of Endocrinology, Diabetes and Metabolism of the Johns Hopkins University School of Medicine, Petersburg, Florida, United States of America
| | - Xianlin Han
- The Sam & Ann Barshop Institute for Longevity & Aging Studies, University of Texas Health Science Center, San Antonio, Texas, United States of America
| | - Gad Asher
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel
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Hou P, Fang J, Liu Z, Shi Y, Agostini M, Bernassola F, Bove P, Candi E, Rovella V, Sica G, Sun Q, Wang Y, Scimeca M, Federici M, Mauriello A, Melino G. Macrophage polarization and metabolism in atherosclerosis. Cell Death Dis 2023; 14:691. [PMID: 37863894 PMCID: PMC10589261 DOI: 10.1038/s41419-023-06206-z] [Citation(s) in RCA: 73] [Impact Index Per Article: 36.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 09/27/2023] [Accepted: 09/29/2023] [Indexed: 10/22/2023]
Abstract
Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of fatty deposits in the inner walls of vessels. These plaques restrict blood flow and lead to complications such as heart attack or stroke. The development of atherosclerosis is influenced by a variety of factors, including age, genetics, lifestyle, and underlying health conditions such as high blood pressure or diabetes. Atherosclerotic plaques in stable form are characterized by slow growth, which leads to luminal stenosis, with low embolic potential or in unstable form, which contributes to high risk for thrombotic and embolic complications with rapid clinical onset. In this complex scenario of atherosclerosis, macrophages participate in the whole process, including the initiation, growth and eventually rupture and wound healing stages of artery plaque formation. Macrophages in plaques exhibit high heterogeneity and plasticity, which affect the evolving plaque microenvironment, e.g., leading to excessive lipid accumulation, cytokine hyperactivation, hypoxia, apoptosis and necroptosis. The metabolic and functional transitions of plaque macrophages in response to plaque microenvironmental factors not only influence ongoing and imminent inflammatory responses within the lesions but also directly dictate atherosclerotic progression or regression. In this review, we discuss the origin of macrophages within plaques, their phenotypic diversity, metabolic shifts, and fate and the roles they play in the dynamic progression of atherosclerosis. It also describes how macrophages interact with other plaque cells, particularly T cells. Ultimately, targeting pathways involved in macrophage polarization may lead to innovative and promising approaches for precision medicine. Further insights into the landscape and biological features of macrophages within atherosclerotic plaques may offer valuable information for optimizing future clinical treatment for atherosclerosis by targeting macrophages.
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Affiliation(s)
- Pengbo Hou
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, Rome, Italy
- The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, China
| | - Jiankai Fang
- The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, China
| | - Zhanhong Liu
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, Rome, Italy
- The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, China
| | - Yufang Shi
- The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, China
| | - Massimiliano Agostini
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, Rome, Italy
| | - Francesca Bernassola
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, Rome, Italy
| | - Pierluigi Bove
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, Rome, Italy
| | - Eleonora Candi
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, Rome, Italy
| | - Valentina Rovella
- Department of System Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Giuseppe Sica
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, Rome, Italy
| | - Qiang Sun
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, Rome, Italy
- The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, China
| | - Ying Wang
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, Rome, Italy
- The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, China
| | - Manuel Scimeca
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, Rome, Italy
| | - Massimo Federici
- Department of System Medicine, University of Rome Tor Vergata, Rome, Italy.
| | - Alessandro Mauriello
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, Rome, Italy.
| | - Gerry Melino
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, Rome, Italy.
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10
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Li K, Li K, He Y, Liang S, Shui X, Lei W. Aryl hydrocarbon receptor: A bridge linking immuno-inflammation and metabolism in atherosclerosis. Biochem Pharmacol 2023; 216:115744. [PMID: 37579858 DOI: 10.1016/j.bcp.2023.115744] [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: 05/26/2023] [Revised: 08/08/2023] [Accepted: 08/09/2023] [Indexed: 08/16/2023]
Abstract
Cardiovascular disease is the leading cause of death worldwide, and atherosclerosis is a major contributor to this etiology. The ligand-activated transcription factor, known as the aryl hydrocarbon receptor (AhR), plays an essential role in the interactions between genes and the environment. In a number of human diseases, including atherosclerosis, the AhR signaling pathway has recently been shown to be aberrantly expressed and activated. It's reported that AhR can regulate the immuno-inflammatory response and metabolism pathways in atherosclerosis, potentially serving as a bridge that links these processes. In this review, we highlight the involvement of AhR in atherosclerosis. From the literature, we conclude that AhR is a potential target for controlling atherosclerosis through precise interventions.
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Affiliation(s)
- Kongwei Li
- Guangdong Provincial Engineering Technology Research Center for Molecular Diagnosis and Innovative Drugs Translation of Cardiopulmonary Vascular Diseases, University Joint Laboratory of Guangdong Province and Macao Region on Molecular Targets and Intervention of Cardiovascular Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China; Cardiovascular Medicine Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China; Department of Precision Laboratory, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Kaiyue Li
- Guangdong Provincial Engineering Technology Research Center for Molecular Diagnosis and Innovative Drugs Translation of Cardiopulmonary Vascular Diseases, University Joint Laboratory of Guangdong Province and Macao Region on Molecular Targets and Intervention of Cardiovascular Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China; Department of Precision Laboratory, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Yuan He
- Guangdong Provincial Engineering Technology Research Center for Molecular Diagnosis and Innovative Drugs Translation of Cardiopulmonary Vascular Diseases, University Joint Laboratory of Guangdong Province and Macao Region on Molecular Targets and Intervention of Cardiovascular Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China; Laboratory of Cardiovascular Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Shan Liang
- Guangdong Provincial Engineering Technology Research Center for Molecular Diagnosis and Innovative Drugs Translation of Cardiopulmonary Vascular Diseases, University Joint Laboratory of Guangdong Province and Macao Region on Molecular Targets and Intervention of Cardiovascular Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China; Cardiovascular Medicine Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China; Department of Precision Laboratory, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Xiaorong Shui
- Guangdong Provincial Engineering Technology Research Center for Molecular Diagnosis and Innovative Drugs Translation of Cardiopulmonary Vascular Diseases, University Joint Laboratory of Guangdong Province and Macao Region on Molecular Targets and Intervention of Cardiovascular Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China; Laboratory of Vascular Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China.
| | - Wei Lei
- Guangdong Provincial Engineering Technology Research Center for Molecular Diagnosis and Innovative Drugs Translation of Cardiopulmonary Vascular Diseases, University Joint Laboratory of Guangdong Province and Macao Region on Molecular Targets and Intervention of Cardiovascular Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China; Department of Precision Laboratory, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China.
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11
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Hu Y, Zhao Y, Li P, Lu H, Li H, Ge J. Hypoxia and panvascular diseases: exploring the role of hypoxia-inducible factors in vascular smooth muscle cells under panvascular pathologies. Sci Bull (Beijing) 2023; 68:1954-1974. [PMID: 37541793 DOI: 10.1016/j.scib.2023.07.032] [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: 04/25/2023] [Revised: 06/13/2023] [Accepted: 07/10/2023] [Indexed: 08/06/2023]
Abstract
As an emerging discipline, panvascular diseases are a set of vascular diseases with atherosclerosis as the common pathogenic hallmark, which mostly affect vital organs like the heart, brain, kidney, and limbs. As the major responser to the most common stressor in the vasculature (hypoxia)-hypoxia-inducible factors (HIFs), and the primary regulator of pressure and oxygen delivery in the vasculature-vascular smooth muscle cells (VSMCs), their own multifaceted nature and their interactions with each other are fascinating. Abnormally active VSMCs (e.g., atherosclerosis, pulmonary hypertension) or abnormally dysfunctional VSMCs (e.g., aneurysms, vascular calcification) are associated with HIFs. These widespread systemic diseases also reflect the interdisciplinary nature of panvascular medicine. Moreover, given the comparable proliferative characteristics exhibited by VSMCs and cancer cells, and the delicate equilibrium between angiogenesis and cancer progression, there is a pressing need for more accurate modulation targets or combination approaches to bolster the effectiveness of HIF targeting therapies. Based on the aforementioned content, this review primarily focused on the significance of integrating the overall and local perspectives, as well as temporal and spatial balance, in the context of the HIF signaling pathway in VSMC-related panvascular diseases. Furthermore, the review discussed the implications of HIF-targeting drugs on panvascular disorders, while considering the trade-offs involved.
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Affiliation(s)
- Yiqing Hu
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China
| | - Yongchao Zhao
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China; Department of Cardiology, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China
| | - Peng Li
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China
| | - Hao Lu
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China; Shanghai Clinical Research Center for Interventional Medicine, Shanghai 200032, China.
| | - Hua Li
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China.
| | - Junbo Ge
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China; Shanghai Clinical Research Center for Interventional Medicine, Shanghai 200032, China; Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai 200032, China; Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai 200032, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China; Department of Cardiology, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China.
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12
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Xue S, Su Z, Liu D. Immunometabolism and immune response regulate macrophage function in atherosclerosis. Ageing Res Rev 2023; 90:101993. [PMID: 37379970 DOI: 10.1016/j.arr.2023.101993] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Accepted: 06/23/2023] [Indexed: 06/30/2023]
Abstract
Macrophages are crucial in the progression of atherosclerotic cardiovascular disease (ASCVD). In the atherosclerotic lesions, macrophages play a central role in maintaining inflammatory response, promoting plaque development, and facilitating thrombosis. Increasing studies indicate that metabolic reprogramming and immune response mediate macrophage functional changes in all stages of atherosclerosis. In this review article, we explain how metabolic changes in glycolysis, oxidative phosphorylation, the tricarboxylic acid cycle, fatty acid synthesis, fatty acid oxidation, and cholesterol metabolism regulate macrophage function in atherosclerosis. We discuss how immune response to oxidized lipids regulate macrophage function in atherosclerosis. Additionally, we explore how abnormal metabolism leads to macrophage mitochondrial dysfunction in atherosclerosis.
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Affiliation(s)
- Sheng Xue
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266003 China.
| | - Zhe Su
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266003 China
| | - Dacheng Liu
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266003 China
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13
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Sun Z, Ji J, Zuo L, Hu Y, Wang K, Xu T, Wang Q, Cheng F. Causal relationship between nonalcoholic fatty liver disease and different sleep traits: a bidirectional Mendelian randomized study. Front Endocrinol (Lausanne) 2023; 14:1159258. [PMID: 37334291 PMCID: PMC10272397 DOI: 10.3389/fendo.2023.1159258] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Accepted: 05/19/2023] [Indexed: 06/20/2023] Open
Abstract
Background and aims Non-alcoholic fatty liver disease(NAFLD) is common worldwide and has previously been reported to be associated with sleep traits. However, it is not clear whether NAFLD changes sleep traits or whether the changes in sleep traits lead to the onset of NAFLD. The purpose of this study was to investigate the causal relationship between NAFLD and changes in sleep traits using Mendelian randomization. Methods We proposed a bidirectional Mendelian randomization (MR) analysis and performed validation analyses to dissect the association between NAFLD and sleep traits. Genetic instruments were used as proxies for NAFLD and sleep. Data of genome-wide association study(GWAS) were obtained from the center for neurogenomics and cognitive research database, Open GWAS database and GWAS catalog. Three MR methods were performed, including inverse variance weighted method(IVW), MR-Egger, weighted median. Results In total,7 traits associated with sleep and 4 traits associated with NAFLD are used in this study. A total of six results showed significant differences. Insomnia was associated with NAFLD (OR(95% CI)= 2.25(1.18,4.27), P = 0.01), Alanine transaminase levels (OR(95% CI)= 2.79(1.70, 4.56), P =4.71×10-5) and percent liver fat(OR(95% CI)= 1.31(1.03,1.69), P = 0.03). Snoring was associated with percent liver fat (1.15(1.05,1.26), P =2×10-3), alanine transaminase levels (OR(95% CI)= 1.27(1.08,1.50), P =0.04).And dozing was associated with percent liver fat(1.14(1.02,1.26), P =0.02).For the remaining 50 outcomes, no significant or definitive association was yielded in MR analysis. Conclusion Genetic evidence suggests putative causal relationships between NAFLD and a set of sleep traits, indicating that sleep traits deserves high priority in clinical practice. Not only the confirmed sleep apnea syndrome, but also the sleep duration and sleep state (such as insomnia) deserve clinical attention. Our study proves that the causal relationship between sleep characteristics and NAFLD is the cause of the change of sleep characteristics, while the onset of non-NAFLD is the cause of the change of sleep characteristics, and the causal relationship is one-way.
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14
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Qiu B, Yuan P, Du X, Jin H, Du J, Huang Y. Hypoxia inducible factor-1α is an important regulator of macrophage biology. Heliyon 2023; 9:e17167. [PMID: 37484306 PMCID: PMC10361316 DOI: 10.1016/j.heliyon.2023.e17167] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 05/13/2023] [Accepted: 06/08/2023] [Indexed: 07/25/2023] Open
Abstract
Hypoxia-inducible factor-1 (HIF-1), a heterodimeric transcription factor composed of the α and β subunits, regulates cellular adaptive responses to hypoxia. Macrophages, which are derived from monocytes, function as antigen-presenting cells that activate various immune responses. HIF-1α regulates the immune response, viability, migration, phenotypic plasticity, and metabolism of macrophages. Specifically, macrophage-derived HIF-1α can prevent excessive pro-inflammatory responses by attenuating the transcriptional activity of nuclear factor-kappa B in vivo and in vitro. HIF-1α modulates macrophage migration by inducing the release of various chemokines and providing necessary energy. HIF-1α promotes macrophage M1 polarization by targeting glucose metabolism. Additionally, HIF-1α induces the upregulation of glycolysis-related enzymes and intermediates of the tricarboxylic acid cycle and pentose phosphate pathway. HIF-1α promotes macrophage apoptosis, necroptosis and reduces autophagy. The current review highlights the mechanisms associated with the regulation of HIF-1α stabilization in macrophages as well as the role of HIF-1α in modulating the physiological functions of macrophages.
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Affiliation(s)
- Bingquan Qiu
- Department of Pediatrics, Peking University First Hospital, Beijing, 100034, China
- State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, 100191, China
| | - Piaoliu Yuan
- Department of Pediatrics, Peking University First Hospital, Beijing, 100034, China
- State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, 100191, China
| | - Xiaojuan Du
- Department of Pediatrics, Peking University First Hospital, Beijing, 100034, China
- State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, 100191, China
| | - Hongfang Jin
- Department of Pediatrics, Peking University First Hospital, Beijing, 100034, China
- State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, 100191, China
| | - Junbao Du
- Department of Pediatrics, Peking University First Hospital, Beijing, 100034, China
- State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, 100191, China
| | - Yaqian Huang
- Department of Pediatrics, Peking University First Hospital, Beijing, 100034, China
- State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, 100191, China
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15
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Shen L, Chen W, Ding J, Shu G, Chen M, Zhao Z, Xia S, Ji J. The role of metabolic reprogramming of oxygen-induced macrophages in the dynamic changes of atherosclerotic plaques. FASEB J 2023; 37:e22791. [PMID: 36723768 DOI: 10.1096/fj.202201486r] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 01/03/2023] [Accepted: 01/12/2023] [Indexed: 02/02/2023]
Abstract
Atherosclerosis (As) is a chronic vascular inflammatory disease. Macrophages are the most important immune cells in atherosclerotic plaques, and the phenotype of plaque macrophages shifts dynamically to adapt to changes in the plaque microenvironment. The aerobic microenvironment of early atherosclerotic plaques promotes the transformation of M2/alternatively activated macrophages mainly through oxidative phosphorylation; the anoxic microenvironment of advanced atherosclerotic plaques mainly promotes the formation of M1/classically activated macrophages through anaerobic glycolysis; and the adventitia angiogenesis of aged atherosclerotic plaques leads to an increase in the proportion of M2/M1 macrophages. Therefore, this review deeply elucidates the dynamic change mechanism of plaque macrophages and the regulation of plaque oxygen content and immune metabolism to find new targets for the treatment of As.
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Affiliation(s)
- Lin Shen
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, China.,Department of Interventional Radiology, Clinical College of the Affiliated Central Hospital of Lishui University, Lishui, China
| | - Weiyue Chen
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, China.,Department of Interventional Radiology, Clinical College of the Affiliated Central Hospital of Lishui University, Lishui, China
| | - Jiayi Ding
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, China.,Department of Interventional Radiology, Clinical College of the Affiliated Central Hospital of Lishui University, Lishui, China
| | - Gaofeng Shu
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, China.,Department of Interventional Radiology, Clinical College of the Affiliated Central Hospital of Lishui University, Lishui, China
| | - Minjiang Chen
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, China.,Department of Interventional Radiology, Clinical College of the Affiliated Central Hospital of Lishui University, Lishui, China
| | - Zhongwei Zhao
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, China.,Department of Interventional Radiology, Clinical College of the Affiliated Central Hospital of Lishui University, Lishui, China
| | - Shuiwei Xia
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, China.,Department of Interventional Radiology, Clinical College of the Affiliated Central Hospital of Lishui University, Lishui, China
| | - Jiansong Ji
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, China.,Department of Interventional Radiology, Clinical College of the Affiliated Central Hospital of Lishui University, Lishui, China
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16
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Yang X, Ma L, Zhang J, Chen L, Zou Z, Shen D, He H, Zhang L, Chen J, Yuan Z, Qin X, Yu C. Hypofucosylation of Unc5b regulated by Fut8 enhances macrophage emigration and prevents atherosclerosis. Cell Biosci 2023; 13:13. [PMID: 36670464 PMCID: PMC9854080 DOI: 10.1186/s13578-023-00959-y] [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: 06/13/2022] [Accepted: 01/08/2023] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND Atherosclerosis (AS) is the leading underlying cause of the majority of clinical cardiovascular events. Retention of foamy macrophages in plaques is the main factor initiating and promoting the atherosclerotic process. Our previous work showed that ox-LDL induced macrophage retention in plaques and that the guidance receptor Uncoordinated-5 homolog B (Unc5b) was involved in this process. However, little is known about the role of Unc5b in regulating macrophage accumulation within plaques. RESULTS In the present study, we found that Unc5b controls macrophage migration and thus promotes plaque progression in ApoE-/- mice. The immunofluorescence colocalization assay results first suggested that fucosyltransferase 8 (Fut8) might participate in the exacerbation of atherosclerosis. Animals with Unc5b overexpression showed elevated levels of Fut8 and numbers of macrophages and an increased lesion size and intimal thickness. However, these effects were reversed in ApoE-/- mice with Unc5b knockdown. Furthermore, Raw264.7 macrophages with siRNA-mediated silencing of Unc5b or overexpression of Unc5b were used to confirm the regulatory mechanisms of Unc5b and Fut8 in vitro. In response to ox-LDL exposure, Unc5b and Fut8 were both upregulated, and macrophages showed reduced pseudopod formation and migratory capacities. However, these capacities were restored by blocking Unc5b or Fut8. Furthermore, the IP assay indicated that Fut8 regulated the level of α-1,6 fucosylation of Unc5b, which mainly occurs in the endoplasmic reticulum (ER), and genetic deletion of the main fucosylation sites or Fut8 resulted in hypofucosylation of Unc5b. Moreover, the macrophage migration mediated by Unc5b depended on inactivation of the p-CDC42/p-PAK pathway. Conversely, macrophages with Unc5b overexpression displayed activation of the p-CDC42/p-PAK pathway and decreased migration both in vivo and in vitro. CONCLUSION These results demonstrated that hypofucosylation of Unc5b regulated by Fut8 is positively associated with the delay of the atherosclerotic process by promoting the migration of foamy macrophages. These findings identify a promising therapeutic target for atherosclerosis.
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Affiliation(s)
- Xi Yang
- grid.203458.80000 0000 8653 0555Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016 China ,grid.410612.00000 0004 0604 6392College of Basic Medicine, Inner Mongolia Medical University, Hohhot, 010110 China
| | - Limei Ma
- grid.203458.80000 0000 8653 0555College of Pharmacy, Chongqing Medical University, Chongqing, 400016 China
| | - Jun Zhang
- grid.203458.80000 0000 8653 0555Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016 China
| | - Linmu Chen
- grid.203458.80000 0000 8653 0555Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016 China
| | - Zhen Zou
- grid.203458.80000 0000 8653 0555Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016 China
| | - Di Shen
- grid.203458.80000 0000 8653 0555Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016 China
| | - Hui He
- grid.203458.80000 0000 8653 0555Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016 China
| | - Lei Zhang
- grid.203458.80000 0000 8653 0555College of Pharmacy, Chongqing Medical University, Chongqing, 400016 China
| | - Jun Chen
- grid.203458.80000 0000 8653 0555College of Pharmacy, Chongqing Medical University, Chongqing, 400016 China
| | - Zhiyi Yuan
- grid.203458.80000 0000 8653 0555College of Pharmacy, Chongqing Medical University, Chongqing, 400016 China
| | - Xia Qin
- grid.203458.80000 0000 8653 0555College of Pharmacy, Chongqing Medical University, Chongqing, 400016 China
| | - Chao Yu
- grid.203458.80000 0000 8653 0555College of Pharmacy, Chongqing Medical University, Chongqing, 400016 China
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17
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Coates HW, Capell-Hattam IM, Olzomer EM, Du X, Farrell R, Yang H, Byrne FL, Brown AJ. Hypoxia truncates and constitutively activates the key cholesterol synthesis enzyme squalene monooxygenase. eLife 2023; 12:82843. [PMID: 36655986 PMCID: PMC9851614 DOI: 10.7554/elife.82843] [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: 08/19/2022] [Accepted: 12/13/2022] [Indexed: 01/20/2023] Open
Abstract
Cholesterol synthesis is both energy- and oxygen-intensive, yet relatively little is known of the regulatory effects of hypoxia on pathway enzymes. We previously showed that the rate-limiting and first oxygen-dependent enzyme of the committed cholesterol synthesis pathway, squalene monooxygenase (SM), can undergo partial proteasomal degradation that renders it constitutively active. Here, we show hypoxia is a physiological trigger for this truncation, which occurs through a two-part mechanism: (1) increased targeting of SM to the proteasome via stabilization of the E3 ubiquitin ligase MARCHF6 and (2) accumulation of the SM substrate, squalene, which impedes the complete degradation of SM and liberates its truncated form. This preserves SM activity and downstream pathway flux during hypoxia. These results uncover a feedforward mechanism that allows SM to accommodate fluctuating substrate levels and may contribute to its widely reported oncogenic properties.
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Affiliation(s)
- Hudson W Coates
- School of Biotechnology and Biomolecular Sciences, UNSW SydneySydneyAustralia
| | | | - Ellen M Olzomer
- School of Biotechnology and Biomolecular Sciences, UNSW SydneySydneyAustralia
| | - Ximing Du
- School of Biotechnology and Biomolecular Sciences, UNSW SydneySydneyAustralia
| | - Rhonda Farrell
- Prince of Wales Private HospitalRandwickAustralia
- Chris O’Brien LifehouseCamperdownAustralia
| | - Hongyuan Yang
- School of Biotechnology and Biomolecular Sciences, UNSW SydneySydneyAustralia
| | - Frances L Byrne
- School of Biotechnology and Biomolecular Sciences, UNSW SydneySydneyAustralia
| | - Andrew J Brown
- School of Biotechnology and Biomolecular Sciences, UNSW SydneySydneyAustralia
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18
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Norda S, Papadantonaki R. Regulation of cells of the arterial wall by hypoxia and its role in the development of atherosclerosis. VASA 2023; 52:6-21. [PMID: 36484144 DOI: 10.1024/0301-1526/a001044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The cell's response to hypoxia depends on stabilization of the hypoxia-inducible factor 1 complex and transactivation of nuclear factor kappa-B (NF-κB). HIF target gene transcription in cells resident to atherosclerotic lesions adjoins a complex interplay of cytokines and mediators of inflammation affecting cholesterol uptake, migration, and inflammation. Maladaptive activation of the HIF-pathway and transactivation of nuclear factor kappa-B causes monocytes to invade early atherosclerotic lesions, maintaining inflammation and aggravating a low-oxygen environment. Meanwhile HIF-dependent upregulation of the ATP-binding cassette transporter ABCA1 causes attenuation of cholesterol efflux and ultimately macrophages becoming foam cells. Hypoxia facilitates neovascularization by upregulation of vascular endothelial growth factor (VEGF) secreted by endothelial cells and vascular smooth muscle cells lining the arterial wall destabilizing the plaque. HIF-knockout animal models and inhibitor studies were able to show beneficial effects on atherogenesis by counteracting the HIF-pathway in the cell wall. In this review the authors elaborate on the up-to-date literature on regulation of cells of the arterial wall through activation of HIF-1α and its effect on atherosclerotic plaque formation.
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Affiliation(s)
- Stephen Norda
- Department of Cardiovascular Medicine, University Hospital Münster, Germany
| | - Rosa Papadantonaki
- Emergency Department, West Middlesex University Hospital, Chelsea and Westminster NHS Trust, London, United Kingdom
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19
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Florance I, Ramasubbu S. Current Understanding on the Role of Lipids in Macrophages and Associated Diseases. Int J Mol Sci 2022; 24:ijms24010589. [PMID: 36614031 PMCID: PMC9820199 DOI: 10.3390/ijms24010589] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Revised: 11/30/2022] [Accepted: 12/09/2022] [Indexed: 12/31/2022] Open
Abstract
Lipid metabolism is the major intracellular mechanism driving a variety of cellular functions such as energy storage, hormone regulation and cell division. Lipids, being a primary component of the cell membrane, play a pivotal role in the survival of macrophages. Lipids are crucial for a variety of macrophage functions including phagocytosis, energy balance and ageing. However, functions of lipids in macrophages vary based on the site the macrophages are residing at. Lipid-loaded macrophages have recently been emerging as a hallmark for several diseases. This review discusses the significance of lipids in adipose tissue macrophages, tumor-associated macrophages, microglia and peritoneal macrophages. Accumulation of macrophages with impaired lipid metabolism is often characteristically observed in several metabolic disorders. Stress signals differentially regulate lipid metabolism. While conditions such as hypoxia result in accumulation of lipids in macrophages, stress signals such as nutrient deprivation initiate lipolysis and clearance of lipids. Understanding the biology of lipid accumulation in macrophages requires the development of potentially active modulators of lipid metabolism.
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Aranda JF, Pérez-García A, Torrecilla-Parra M, Fernández-de Frutos M, Martín-Martín Y, Mateos-Gómez PA, Pardo-Marqués V, Busto R, Ramírez CM. Role of miR-199a-5p in the post-transcriptional regulation of ABCA1 in response to hypoxia in peritoneal macrophages. Front Cardiovasc Med 2022; 9:994080. [PMID: 36407436 PMCID: PMC9669644 DOI: 10.3389/fcvm.2022.994080] [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] [Received: 07/14/2022] [Accepted: 10/19/2022] [Indexed: 01/03/2025] Open
Abstract
Hypoxia is a crucial factor contributing to maintenance of atherosclerotic lesions. The ability of ABCA1 to stimulate the efflux of cholesterol from cells in the periphery, particularly foam cells in atherosclerotic plaques, is an important anti-atherosclerotic mechanism. The posttranscriptional regulation by miRNAs represents a key regulatory mechanism of a number of signaling pathways involved in atherosclerosis. Previously, miR-199a-5p has been shown to be implicated in the endocytic and retrograde intracellular transport. Although the regulation of miR-199a-5p and ABCA1 by hypoxia has been already reported independently, the role of miR-199a-5p in macrophages and its possible role in atherogenic processes such us regulation of lipid homeostasis through ABCA1 has not been yet investigated. Here, we demonstrate that both ABCA1 and miR-199a-5p show an inverse regulation by hypoxia and Ac-LDL in primary macrophages. Moreover, we demonstrated that miR-199a-5p regulates ABCA1 mRNA and protein levels by directly binding to its 3'UTR. As a result, manipulation of cellular miR-199a-5p levels alters ABCA1 expression and cholesterol efflux in primary mouse macrophages. Taken together, these results indicate that the correlation between ABCA1-miR-199a-5p could be exploited to control macrophage cholesterol efflux during the onset of atherosclerosis, where cholesterol alterations and hypoxia play a pathogenic role.
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Affiliation(s)
- Juan Francisco Aranda
- Department of Basic Medical Sciences, CEU San Pablo University, CEU Universities, Madrid, Spain
| | - Ana Pérez-García
- IMDEA Research Institute of Food and Health Sciences, Madrid, Spain
| | | | | | | | - Pedro A. Mateos-Gómez
- Department of Systems Biology, School of Medicine and Health Sciences, University of Alcalá, Madrid, Spain
| | | | - Rebeca Busto
- Department of Clinical Biochemistry, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain
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21
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Effects of Six Weeks of Hypoxia Exposure on Hepatic Fatty Acid Metabolism in ApoE Knockout Mice Fed a High-Fat Diet. LIFE (BASEL, SWITZERLAND) 2022; 12:life12101535. [PMID: 36294970 PMCID: PMC9605121 DOI: 10.3390/life12101535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 09/08/2022] [Accepted: 09/28/2022] [Indexed: 11/05/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease with a characteristic of abnormal lipid metabolism. In the present study, we employed apolipoprotein E knockout (ApoE KO) mice to investigate the effects of hypoxia exposure on hepatic fatty acid metabolism and to test whether a high-fat diet (HFD) would suppress the beneficial effect caused by hypoxia treatment. ApoE KO mice were fed a HFD for 12 weeks, and then were forwarded into a six-week experiment with four groups: HFD + normoxia, normal diet (ND) + normoxia, HFD + hypoxia exposure (HE), and ND + HE. The C57BL/6J wild type (WT) mice were fed a ND for 18 weeks as the baseline control. The hypoxia exposure was performed in daytime with normobaric hypoxia (11.2% oxygen, 1 h per time, three times per week). Body weight, food and energy intake, plasma lipid profiles, hepatic lipid contents, plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and molecular/biochemical makers and regulators of the fatty acid synthesis and oxidation in the liver were measured at the end of interventions. Six weeks of hypoxia exposure decreased plasma triglycerides (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) contents but did not change hepatic TG and non-esterified fatty acid (NEFA) levels in ApoE KO mice fed a HFD or ND. Furthermore, hypoxia exposure decreased the mRNA expression of Fasn, Scd1, and Srebp-1c significantly in the HFD + HE group compared with those in the HFD + normoxia group; after replacing a HFD with a ND, hypoxia treatment achieved more significant changes in the measured variables. In addition, the protein expression of HIF-1α was increased only in the ND + HE group but not in the HFD + HE group. Even though hypoxia exposure did not affect hepatic TG and NEFA levels, at the genetic level, the intervention had significant effects on hepatic metabolic indices of fatty acid synthesis, especially in the ND + HE group, while HFD suppressed the beneficial effect of hypoxia on hepatic lipid metabolism in male ApoE KO mice. The dietary intervention of shifting HFD to ND could be more effective in reducing hepatic lipid accumulation than hypoxia intervention.
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22
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Makaritsis KP, Kotidis C, Papacharalampous K, Kouvaras E, Poulakida E, Tarantilis P, Asprodini E, Ntaios G, Koukoulis GΚ, Dalekos GΝ, Ioannou M. Mechanistic insights on the effect of crocin, an active ingredient of saffron, on atherosclerosis in apolipoprotein E knockout mice. Coron Artery Dis 2022; 33:394-402. [PMID: 35880561 DOI: 10.1097/mca.0000000000001142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND We investigated the effect of crocin treatment on atherosclerosis and serum lipids in apolipoprotein E knockout (ApoE-/-) mice, focusing on the expression of endothelial nitric oxide synthase (eNOS) and hypoxia-induced factor-1 alpha (HIF-1α). METHODS Sixty-two animals were divided into two groups and randomly allocated to crocin (100 mg/kg/day) in drinking water or no crocin. All mice were maintained on standard chow diet containing 5% fat. Crocin was initiated at the 16th week of age and continued for 16 additional weeks. At 32 weeks of age, after blood sampling for plasma lipid determination and euthanasia, proximal aorta was removed and 3 μm sections were used to measure the atherosclerotic area and determine the expression of eNOS and HIF-1α by immunohistochemistry. RESULTS Each group consisted of 31 animals (17 males and 14 females in each group). Crocin significantly reduced the atherosclerotic area (mm2 ± SEM) in treated mice compared to controls, both in males (0.0798 ± 0.017 vs. 0.1918 ± 0.028, P < 0.002, respectively) and females (0.0986 ± 0.023 vs. 0.1765 ± 0.025, P < 0.03, respectively). eNOS expression was significantly increased in crocin-treated mice compared to controls, both in males (2.77 ± 0.24 vs. 1.50 ± 0.34, P=0.004, respectively) and females (3.41 ± 0.37 vs. 1.16 ± 0.44, P=0.003, respectively). HIF-1α expression was significantly decreased in crocin-treated mice compared to controls, both in males (21.25 ± 2.14 vs. 156.5 ± 6.67, P < 0.001, respectively) and females (35.3 ± 7.20 vs. 113.3 ± 9.0, P < 0.01, respectively). No difference was noticed in total, low- and high-density lipoprotein cholesterol between treated and control mice. CONCLUSION Crocin reduces atherosclerosis possibly by modulation of eNOS and HIF-1α expression in ApoE-/- mice without affecting plasma cholesterol.
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Affiliation(s)
- Konstantinos P Makaritsis
- Department of Medicine & Research Laboratory of Internal Medicine, Faculty of Medicine, University of Thessaly, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
| | - Charalampos Kotidis
- Department of Medicine & Research Laboratory of Internal Medicine, Faculty of Medicine, University of Thessaly, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
- East Midlands Congenital Heart Centre, University Hospitals of Leicester, Leicester, UK
| | | | - Evangelos Kouvaras
- Department of Pathology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa
| | - Eirini Poulakida
- Department of Medicine & Research Laboratory of Internal Medicine, Faculty of Medicine, University of Thessaly, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
| | - Petros Tarantilis
- Laboratory of Chemistry, Department of Food Science & Human Nutrition, School of Food Biotechnology and Development, Agricultural University of Athens, Athens
| | - Eftichia Asprodini
- Laboratory of Pharmacology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - George Ntaios
- Department of Medicine & Research Laboratory of Internal Medicine, Faculty of Medicine, University of Thessaly, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
| | - George Κ Koukoulis
- Department of Pathology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa
| | - George Ν Dalekos
- Department of Medicine & Research Laboratory of Internal Medicine, Faculty of Medicine, University of Thessaly, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
| | - Maria Ioannou
- Department of Pathology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa
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23
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Zhang X, Rotllan N, Canfrán-Duque A, Sun J, Toczek J, Moshnikova A, Malik S, Price NL, Araldi E, Zhong W, Sadeghi MM, Andreev OA, Bahal R, Reshetnyak YK, Suárez Y, Fernández-Hernando C. Targeted Suppression of miRNA-33 Using pHLIP Improves Atherosclerosis Regression. Circ Res 2022; 131:77-90. [PMID: 35534923 PMCID: PMC9640270 DOI: 10.1161/circresaha.121.320296] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 05/03/2022] [Indexed: 11/16/2022]
Abstract
BACKGROUND miRNA therapeutics have gained attention during the past decade. These oligonucleotide treatments can modulate the expression of miRNAs in vivo and could be used to correct the imbalance of gene expression found in human diseases such as obesity, metabolic syndrome, and atherosclerosis. The in vivo efficacy of current anti-miRNA technologies hindered by physiological and cellular barriers to delivery into targeted cells and the nature of miRNAs that allows one to target an entire pathway that may lead to deleterious off-target effects. For these reasons, novel targeted delivery systems to inhibit miRNAs in specific tissues will be important for developing effective therapeutic strategies for numerous diseases including atherosclerosis. METHODS We used pH low-insertion peptide (pHLIP) constructs as vehicles to deliver microRNA-33-5p (miR-33) antisense oligonucleotides to atherosclerotic plaques. Immunohistochemistry and histology analysis was performed to assess the efficacy of miR-33 silencing in atherosclerotic lesions. We also assessed how miR-33 inhibition affects gene expression in monocytes/macrophages by single-cell RNA transcriptomics. RESULTS The anti-miR-33 conjugated pHLIP constructs are preferentially delivered to atherosclerotic plaque macrophages. The inhibition of miR-33 using pHLIP-directed macrophage targeting improves atherosclerosis regression by increasing collagen content and decreased lipid accumulation within vascular lesions. Single-cell RNA sequencing analysis revealed higher expression of fibrotic genes (Col2a1, Col3a1, Col1a2, Fn1, etc) and tissue inhibitor of metalloproteinase 3 (Timp3) and downregulation of Mmp12 in macrophages from atherosclerotic lesions targeted by pHLIP-anti-miR-33. CONCLUSIONS This study provides proof of principle for the application of pHLIP for treating advanced atherosclerosis via pharmacological inhibition of miR-33 in macrophages that avoid the deleterious effects in other metabolic tissues. This may open new therapeutic opportunities for atherosclerosis-associated cardiovascular diseases via selective delivery of other protective miRNAs.
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Affiliation(s)
- Xinbo Zhang
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut, USA
- Integrative Cell Signaling and Neurobiology of Metabolism Program, Department of Comparative Medicine and Department of Pathology, 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
- Integrative Cell Signaling and Neurobiology of Metabolism Program, Department of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Alberto Canfrán-Duque
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut, USA
- Integrative Cell Signaling and Neurobiology of Metabolism Program, Department of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Jonathan Sun
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut, USA
- Integrative Cell Signaling and Neurobiology of Metabolism Program, Department of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Jakub Toczek
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut, USA
- Cardiovascular Molecular Imaging Laboratory, Section of Cardiovascular Medicine and Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut, USA
- Section of Cardiology, Veterans Affairs Connecticut Healthcare System, West Haven, CT, USA
| | - Anna Moshnikova
- Department Physics, University of Rhode Island, Kingston, Rhode Island, USA
| | - Shipra Malik
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut, USA
| | - Nathan L. Price
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut, USA
- Integrative Cell Signaling and Neurobiology of Metabolism Program, Department of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Elisa Araldi
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut, USA
- Integrative Cell Signaling and Neurobiology of Metabolism Program, Department of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Wen Zhong
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut, USA
- Integrative Cell Signaling and Neurobiology of Metabolism Program, Department of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Mehran M. Sadeghi
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut, USA
- Cardiovascular Molecular Imaging Laboratory, Section of Cardiovascular Medicine and Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut, USA
- Section of Cardiology, Veterans Affairs Connecticut Healthcare System, West Haven, CT, USA
| | - Oleg A. Andreev
- Department Physics, University of Rhode Island, Kingston, Rhode Island, USA
| | - Raman Bahal
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut, USA
| | - Yana K. Reshetnyak
- Department Physics, University of Rhode Island, Kingston, Rhode Island, USA
| | - Yajaira Suárez
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut, USA
- Integrative Cell Signaling and Neurobiology of Metabolism Program, Department of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Carlos Fernández-Hernando
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut, USA
- Integrative Cell Signaling and Neurobiology of Metabolism Program, Department of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA
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24
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Christoph M, Pflücke C, Mensch M, Augstein A, Jellinghaus S, Ende G, Mierke J, Franke K, Wielockx B, Ibrahim K, Poitz DM. Myeloid PHD2 deficiency accelerates neointima formation via Hif-1α. Mol Immunol 2022; 149:48-58. [PMID: 35724581 DOI: 10.1016/j.molimm.2022.06.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 06/04/2022] [Accepted: 06/08/2022] [Indexed: 11/26/2022]
Abstract
The key players of the hypoxic response are the hypoxia-inducible factors (Hif), whose α-subunits are tightly regulated by Prolyl-4-hydroxylases (PHD), predominantly by PHD2. Monocytes/Macrophages are involved in atherosclerosis but also restenosis and were found at hypoxic and sites of the lesion. Little is known about the role of the myeloid PHD2 in atherosclerosis and neointima formation. The study aimed to investigate the consequences of a myeloid deficiency of PHD2 in the process of neointima formation using an arterial denudation model. LysM-cre mice were crossed with PHD2fl/fl, PHD2fl/fl/Hif1αfl/fl and PHD2fl/fl/Hif2αfl/fl to get myeloid specific knockout of PHD2 and the Hif-α subunits. Denudation of the femoral artery was performed and animals were fed a western type diet afterwards with analysis of neointima formation 5 and 35 days after denudation. Increased neointima formation in myeloid PHD2 knockouts was observed, which was blunted by double-knockout of PHD2 and Hif1α whereas double knockout of PHD2 and Hif-2α showed comparable lesions to the PHD2 knockouts. Macrophage infiltration was comparable to the neointima formation, suggesting a more inflammatory reaction, and was accompanied by increased intimal VEGF-A expression. Collagen-content inversely correlated to the extent of neointima formation suggesting a destabilization of the plaque. This effect might be triggered by macrophage polarization. Therefore, in vitro results showed a distinct expression pattern in differentially polarized macrophages with high expression of Hif-1α, VEGF and MMP-1 in proinflammatory M1 macrophages. In conclusion, the results show that myeloid Hif-1α is involved in neointima hyperplasia. Our in vivo and in vitro data reveal a central role for this transcription factor in driving plaque-vascularization accompanied by matrix-degradation leading to plaque destabilization.
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Affiliation(s)
- Marian Christoph
- Internal Medicine and Cardiology, Heart Center Dresden, University Hospital at the Technische Universität, Dresden, Germany; Technische Universität, Dresden Campus, Chemnitz, Germany
| | - Christian Pflücke
- Internal Medicine and Cardiology, Heart Center Dresden, University Hospital at the Technische Universität, Dresden, Germany
| | - Matthias Mensch
- Internal Medicine and Cardiology, Heart Center Dresden, University Hospital at the Technische Universität, Dresden, Germany
| | - Antje Augstein
- Internal Medicine and Cardiology, Heart Center Dresden, University Hospital at the Technische Universität, Dresden, Germany
| | - Stefanie Jellinghaus
- Internal Medicine and Cardiology, Heart Center Dresden, University Hospital at the Technische Universität, Dresden, Germany
| | - Georg Ende
- Internal Medicine and Cardiology, Heart Center Dresden, University Hospital at the Technische Universität, Dresden, Germany
| | - Johannes Mierke
- Internal Medicine and Cardiology, Heart Center Dresden, University Hospital at the Technische Universität, Dresden, Germany
| | - Kristin Franke
- Institute of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany
| | - Ben Wielockx
- Institute of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany
| | - Karim Ibrahim
- Internal Medicine and Cardiology, Heart Center Dresden, University Hospital at the Technische Universität, Dresden, Germany; Technische Universität, Dresden Campus, Chemnitz, Germany
| | - David M Poitz
- Internal Medicine and Cardiology, Heart Center Dresden, University Hospital at the Technische Universität, Dresden, Germany; Institute of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany.
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25
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Liang S, Sun Q, Du Z, Ren X, Xu Q, Sun Z, Duan J. PM 2.5 induce the defective efferocytosis and promote atherosclerosis via HIF-1α activation in macrophage. Nanotoxicology 2022; 16:290-309. [PMID: 35653618 DOI: 10.1080/17435390.2022.2083995] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Epidemiological studies demonstrate that fine particulate matter (PM2.5) promotes the development of atherosclerosis. However, the mechanism insight of PM2.5-induced atherosclerosis is still lacking. The aim of this study was to explore the biological effects of hypoxia-inducible factor 1α (HIF-1α) on PM2.5-triggered atherosclerosis. The vascular stiffness, carotid intima-media thickness (CIMT), lipid and atherosclerotic lesion were increased when von Hippel-Lindau (VHL)-null mice were exposed to PM2.5. Yet, knockout of HIF-1α markedly decreased the PM2.5-triggered atherosclerotic lesion. We firstly performed microarray analysis in PM2.5-treated bone morrow-derived macrophages (BMDMs), which showed that PM2.5 significantly changed the genes expression patterns and affected biological processes such as phagocytosis, apoptotic cell clearance, cellular response to hypoxia, apoptotic process and inflammatory response. Moreover, the data showed knockout of HIF-1α remarkably relieved PM2.5-induced defective efferocytosis. Mechanistically, PM2.5 inhibited the level of genes and proteins of efferocytosis receptor c-Mer tyrosine kinase (MerTK), especially in VHL-null BMDMs. In addition, PM2.5 increased the genes and proteins of a disintegrin and metallopeptidase domain 17 (ADAM17), which caused the MerTK cleavage to form soluble MerTK (sMer) in plasma and cellular supernatant. The sMer was significantly up-regulated in plasma of VHL-null PM2.5-exposed mice. Moreover, PM2.5 could induce defective efferocytosis and activate inflammatory response through MerTK/IFNAR1/STAT1 signaling pathway in macrophages. Our results demonstrate that PM2.5 could induce defective efferocytosis and inflammation by activating HIF-1α in macrophages, ultimately resulting in accelerating atherosclerotic lesion formation and development. Our data suggest HIF-1α in macrophages might be a potential target for PM2.5-related atherosclerosis.
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Affiliation(s)
- Shuang Liang
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, P.R. China.,Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, P.R. China
| | - Qinglin Sun
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, P.R. China.,Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, P.R. China
| | - Zhou Du
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, P.R. China.,Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, P.R. China
| | - Xiaoke Ren
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, P.R. China.,Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, P.R. China
| | - Qing Xu
- Core Facility Centre, Capital Medical University, Beijing, P.R. China
| | - Zhiwei Sun
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, P.R. China.,Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, P.R. China
| | - Junchao Duan
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, P.R. China.,Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, P.R. China
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26
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Adam CA, Șalaru DL, Prisacariu C, Marcu DTM, Sascău RA, Stătescu C. Novel Biomarkers of Atherosclerotic Vascular Disease-Latest Insights in the Research Field. Int J Mol Sci 2022; 23:4998. [PMID: 35563387 PMCID: PMC9103799 DOI: 10.3390/ijms23094998] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 04/28/2022] [Accepted: 04/29/2022] [Indexed: 02/06/2023] Open
Abstract
The atherosclerotic vascular disease is a cardiovascular continuum in which the main role is attributed to atherosclerosis, from its appearance to its associated complications. The increasing prevalence of cardiovascular risk factors, population ageing, and burden on both the economy and the healthcare system have led to the development of new diagnostic and therapeutic strategies in the field. The better understanding or discovery of new pathophysiological mechanisms and molecules modulating various signaling pathways involved in atherosclerosis have led to the development of potential new biomarkers, with key role in early, subclinical diagnosis. The evolution of technological processes in medicine has shifted the attention of researchers from the profiling of classical risk factors to the identification of new biomarkers such as midregional pro-adrenomedullin, midkine, stromelysin-2, pentraxin 3, inflammasomes, or endothelial cell-derived extracellular vesicles. These molecules are seen as future therapeutic targets associated with decreased morbidity and mortality through early diagnosis of atherosclerotic lesions and future research directions.
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Affiliation(s)
- Cristina Andreea Adam
- Institute of Cardiovascular Diseases “Prof. Dr. George I.M. Georgescu”, 700503 Iași, Romania; (C.A.A.); (C.P.); (R.A.S.); (C.S.)
| | - Delia Lidia Șalaru
- Institute of Cardiovascular Diseases “Prof. Dr. George I.M. Georgescu”, 700503 Iași, Romania; (C.A.A.); (C.P.); (R.A.S.); (C.S.)
- Department of Internal Medicine, University of Medicine and Pharmacy “Grigore T. Popa”, 700115 Iași, Romania;
| | - Cristina Prisacariu
- Institute of Cardiovascular Diseases “Prof. Dr. George I.M. Georgescu”, 700503 Iași, Romania; (C.A.A.); (C.P.); (R.A.S.); (C.S.)
- Department of Internal Medicine, University of Medicine and Pharmacy “Grigore T. Popa”, 700115 Iași, Romania;
| | - Dragoș Traian Marius Marcu
- Department of Internal Medicine, University of Medicine and Pharmacy “Grigore T. Popa”, 700115 Iași, Romania;
| | - Radu Andy Sascău
- Institute of Cardiovascular Diseases “Prof. Dr. George I.M. Georgescu”, 700503 Iași, Romania; (C.A.A.); (C.P.); (R.A.S.); (C.S.)
- Department of Internal Medicine, University of Medicine and Pharmacy “Grigore T. Popa”, 700115 Iași, Romania;
| | - Cristian Stătescu
- Institute of Cardiovascular Diseases “Prof. Dr. George I.M. Georgescu”, 700503 Iași, Romania; (C.A.A.); (C.P.); (R.A.S.); (C.S.)
- Department of Internal Medicine, University of Medicine and Pharmacy “Grigore T. Popa”, 700115 Iași, Romania;
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27
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Thomas C, Leleu D, Masson D. Cholesterol and HIF-1α: Dangerous Liaisons in Atherosclerosis. Front Immunol 2022; 13:868958. [PMID: 35386720 PMCID: PMC8977597 DOI: 10.3389/fimmu.2022.868958] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 02/28/2022] [Indexed: 12/17/2022] Open
Abstract
HIF-1α exerts both detrimental and beneficial actions in atherosclerosis. While there is evidence that HIF-1α could be pro-atherogenic within the atheromatous plaque, experimental models of atherosclerosis suggest a more complex role that depends on the cell type expressing HIF-1α. In atheroma plaques, HIF-1α is stabilized by local hypoxic conditions and by the lipid microenvironment. Macrophage exposure to oxidized LDLs (oxLDLs) or to necrotic plaque debris enriched with oxysterols induces HIF-1α -dependent pathways. Moreover, HIF-1α is involved in many oxLDL-induced effects in macrophages including inflammatory response, angiogenesis and metabolic reprogramming. OxLDLs activate toll-like receptor signaling pathways to promote HIF-1α stabilization. OxLDLs and oxysterols also induce NADPH oxidases and reactive oxygen species production, which subsequently leads to HIF-1α stabilization. Finally, recent investigations revealed that the activation of liver X receptor, an oxysterol nuclear receptor, results in an increase in HIF-1α transcriptional activity. Reciprocally, HIF-1α signaling promotes triglycerides and cholesterol accumulation in macrophages. Hypoxia and HIF-1α increase the uptake of oxLDLs, promote cholesterol and triglyceride synthesis and decrease cholesterol efflux. In conclusion, the impact of HIF-1α on cholesterol homeostasis within macrophages and the feedback activation of the inflammatory response by oxysterols via HIF-1α could play a deleterious role in atherosclerosis. In this context, studies aimed at understanding the specific mechanisms leading to HIF-1α activation within the plaque represents a promising field for research investigations and a path toward development of novel therapies.
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Affiliation(s)
- Charles Thomas
- Univ. Bourgogne Franche-Comté, LNC UMR1231, Dijon, France.,INSERM, LNC UMR1231, Dijon, France.,LipSTIC LabEx, Dijon, France
| | - Damien Leleu
- Univ. Bourgogne Franche-Comté, LNC UMR1231, Dijon, France.,INSERM, LNC UMR1231, Dijon, France.,LipSTIC LabEx, Dijon, France.,CHRU Dijon Bourgogne, Laboratory of Clinical Chemistry, Dijon, France
| | - David Masson
- Univ. Bourgogne Franche-Comté, LNC UMR1231, Dijon, France.,INSERM, LNC UMR1231, Dijon, France.,LipSTIC LabEx, Dijon, France.,CHRU Dijon Bourgogne, Laboratory of Clinical Chemistry, Dijon, France
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Yu B, Wang X, Song Y, Xie G, Jiao S, Shi L, Cao X, Han X, Qu A. The role of hypoxia-inducible factors in cardiovascular diseases. Pharmacol Ther 2022; 238:108186. [PMID: 35413308 DOI: 10.1016/j.pharmthera.2022.108186] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 01/29/2022] [Accepted: 04/06/2022] [Indexed: 12/12/2022]
Abstract
Cardiovascular diseases are the leading cause of death worldwide. During the development of cardiovascular diseases, hypoxia plays a crucial role. Hypoxia-inducible factors (HIFs) are the key transcription factors for adaptive hypoxic responses, which orchestrate the transcription of numerous genes involved in angiogenesis, erythropoiesis, glycolytic metabolism, inflammation, and so on. Recent studies have dissected the precise role of cell-specific HIFs in the pathogenesis of hypertension, atherosclerosis, aortic aneurysms, pulmonary arterial hypertension, and heart failure using tissue-specific HIF-knockout or -overexpressing animal models. More importantly, several compounds developed as HIF inhibitors or activators have been in clinical trials for the treatment of renal cancer or anemia; however, little is known on the therapeutic potential of these inhibitors for cardiovascular diseases. The purpose of this review is to summarize the recent advances on HIFs in the pathogenesis and pathophysiology of cardiovascular diseases and to provide evidence of potential clinical therapeutic targets.
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Affiliation(s)
- Baoqi Yu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, PR China; Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing 100069, PR China
| | - Xia Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, PR China; Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing 100069, PR China
| | - Yanting Song
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, PR China; Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing 100069, PR China; Department of Pathology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, PR China
| | - Guomin Xie
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, PR China; Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing 100069, PR China
| | - Shiyu Jiao
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, PR China; Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing 100069, PR China
| | - Li Shi
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, PR China; Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing 100069, PR China
| | - Xuejie Cao
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, PR China; Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing 100069, PR China
| | - Xinyao Han
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, PR China; Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing 100069, PR China
| | - Aijuan Qu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, PR China; Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing 100069, PR China.
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The correlation between the inflammatory effects of activated macrophages in atherosclerosis and aortic dissection. Ann Vasc Surg 2022; 85:341-346. [PMID: 35395377 DOI: 10.1016/j.avsg.2022.03.027] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 02/14/2022] [Accepted: 03/24/2022] [Indexed: 11/20/2022]
Abstract
OBJECTIVE To study the correlation between lipid metabolism index, inflammatory factor index and M1 macrophage content, and aortic dissection. METHODS Patients with only basic atherosclerotic diseases were selected as the control group, and patients with only basic atherosclerotic diseases and aortic dissection were set as experiment group. Blood of patients was collected. Chemiluminescent immunoassay was applied to determine the concentration of total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL), high density lipoprotein (HDL), apolipoprotein A1 (ApoA1) (ApoA1) and apolipoprotein B1 (ApoB1). ELISA assay was applied to measure the concentration of tumor necrosis factor-α (TNF-α), Interleukin 1β (IL-1β), interleukin-6 (IL-6) and interleukin-10 (IL-10). The content of M1 macrophages in blood was measured with FCM (Flow cytometry) method. The correlation between the inflammatory effects of activated macrophages in atherosclerosis and aortic dissection was analyzed by simple linear regression analysis. RESULTS Concentration of TC, TG, LDL-C and ApoB, and the concentration of TNF-α, IL-1β and IL-6 in experiment group were markedly higher compared to those in the control group, while the concentration of HDL-C and ApoA1, and IL-10 concentration in experiment group was markedly lower. The content of M1 macrophage in the control group was significantly lower compared to experiment group. The proportion of M1 macrophages, concentration of TC, TG, LDL, HDL, ApoA1 and ApoB1, and concentration of TNF-α, IL-1β, IL-6 and IL-10 were all significantly correlated to the occurrence of aortic dissection. CONCLUSION The proportion of M1 macrophages, concentration of TC, TG, LDL, HDL, ApoA1 and ApoB1, and concentration of TNF-α, IL-1β, IL-6 and IL-10 are significantly correlated with the occurrence of aortic dissection.
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Peters F, Ebner LJA, Atac D, Maggi J, Berger W, den Hollander AI, Grimm C. Regulation of ABCA1 by AMD-Associated Genetic Variants and Hypoxia in iPSC-RPE. Int J Mol Sci 2022; 23:ijms23063194. [PMID: 35328615 PMCID: PMC8953808 DOI: 10.3390/ijms23063194] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 03/11/2022] [Accepted: 03/14/2022] [Indexed: 02/04/2023] Open
Abstract
Age-related macular degeneration (AMD) is a progressive disease of the macula characterized by atrophy of the retinal pigment epithelium (RPE) and photoreceptor degeneration, leading to severe vision loss at advanced stages in the elderly population. Impaired reverse cholesterol transport (RCT) as well as intracellular lipid accumulation in the RPE are implicated in AMD pathogenesis. Here, we focus on ATP-binding cassette transporter A1 (ABCA1), a major cholesterol transport protein in the RPE, and analyze conditions that lead to ABCA1 dysregulation in induced pluripotent stem cell (iPSC)-derived RPE cells (iRPEs). Our results indicate that the risk-conferring alleles rs1883025 (C) and rs2740488 (A) in ABCA1 are associated with increased ABCA1 mRNA and protein levels and reduced efficiency of cholesterol efflux from the RPE. Hypoxia, an environmental risk factor for AMD, reduced expression of ABCA1 and increased intracellular lipid accumulation. Treatment with a liver X receptor (LXR) agonist led to an increase in ABCA1 expression and reduced lipid accumulation. Our data strengthen the homeostatic role of cholesterol efflux in the RPE and suggest that increasing cellular cholesterol export by stimulating ABCA1 expression might lessen lipid load, improving RPE survival and reducing the risk of developing AMD.
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Affiliation(s)
- Florian Peters
- Laboratory for Retinal Cell Biology, Department of Ophthalmology, University Hospital Zurich, University of Zurich, 8952 Zurich, Switzerland;
- Correspondence: (F.P.); (C.G.)
| | - Lynn J. A. Ebner
- Laboratory for Retinal Cell Biology, Department of Ophthalmology, University Hospital Zurich, University of Zurich, 8952 Zurich, Switzerland;
| | - David Atac
- Institute of Medical Molecular Genetics, University of Zurich, 8952 Zurich, Switzerland; (D.A.); (J.M.); (W.B.)
| | - Jordi Maggi
- Institute of Medical Molecular Genetics, University of Zurich, 8952 Zurich, Switzerland; (D.A.); (J.M.); (W.B.)
| | - Wolfgang Berger
- Institute of Medical Molecular Genetics, University of Zurich, 8952 Zurich, Switzerland; (D.A.); (J.M.); (W.B.)
| | - Anneke I. den Hollander
- Department of Ophthalmology, Radboud University Medical Center, 6525 Nijmegen, The Netherlands;
- AbbVie, Genomic Research Center, 200 Sidney Street, Cambridge, MA 02139, USA
| | - Christian Grimm
- Laboratory for Retinal Cell Biology, Department of Ophthalmology, University Hospital Zurich, University of Zurich, 8952 Zurich, Switzerland;
- Correspondence: (F.P.); (C.G.)
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Wculek SK, Dunphy G, Heras-Murillo I, Mastrangelo A, Sancho D. Metabolism of tissue macrophages in homeostasis and pathology. Cell Mol Immunol 2022; 19:384-408. [PMID: 34876704 PMCID: PMC8891297 DOI: 10.1038/s41423-021-00791-9] [Citation(s) in RCA: 212] [Impact Index Per Article: 70.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 09/25/2021] [Indexed: 02/06/2023] Open
Abstract
Cellular metabolism orchestrates the intricate use of tissue fuels for catabolism and anabolism to generate cellular energy and structural components. The emerging field of immunometabolism highlights the importance of cellular metabolism for the maintenance and activities of immune cells. Macrophages are embryo- or adult bone marrow-derived leukocytes that are key for healthy tissue homeostasis but can also contribute to pathologies such as metabolic syndrome, atherosclerosis, fibrosis or cancer. Macrophage metabolism has largely been studied in vitro. However, different organs contain diverse macrophage populations that specialize in distinct and often tissue-specific functions. This context specificity creates diverging metabolic challenges for tissue macrophage populations to fulfill their homeostatic roles in their particular microenvironment and conditions their response in pathological conditions. Here, we outline current knowledge on the metabolic requirements and adaptations of macrophages located in tissues during homeostasis and selected diseases.
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Affiliation(s)
- Stefanie K Wculek
- Immunobiology Laboratory, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernández Almagro 3, Madrid, 28029, Spain.
| | - Gillian Dunphy
- Immunobiology Laboratory, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernández Almagro 3, Madrid, 28029, Spain
| | - Ignacio Heras-Murillo
- Immunobiology Laboratory, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernández Almagro 3, Madrid, 28029, Spain
| | - Annalaura Mastrangelo
- Immunobiology Laboratory, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernández Almagro 3, Madrid, 28029, Spain
| | - David Sancho
- Immunobiology Laboratory, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernández Almagro 3, Madrid, 28029, Spain.
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Kong J, Liu L, Song L, Zhao R, Feng Y. MicroRNA miR-34a-5p inhibition restrains oxidative stress injury of macrophages by targeting MDM4. Vascular 2022; 31:608-618. [PMID: 35226569 DOI: 10.1177/17085381211069447] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
OBJECTIVE Atherosclerosis is a chronic cardiovascular disease associated with oxidative stress damage, which is caused by excessive oxidation of low-density lipoprotein (ox-LDL). The role of microRNA miR-34a-5p on oxidative stress in ox-LDL-treated macrophages was investigated in this study. METHODS Flow cytometry was prepared for assessing THP1-derived macrophage apoptosis. The protein and expression levels of miR-34a-5p and MDM4 were examined by Western blot and RT-qPCR, respectively. We also measured the levels of total cholesterol (TC) and triglyceride to determine the lipid accumulation. Subsequently, the activities of superoxide dismutase, malondialdehyde, and reactive oxygen species revealed the level of oxidative stress injury after miR-34a-5p and MDM4 knockdown. RESULTS After ox-LDL treatment, cell apoptosis of macrophages increased in a dose-dependent and time-dependent manner. With the increase of ox-LDL treatment and the prolongation of treatment time, the expression level of miR-34a-5p was upregulated. Next, interfering with miR-34a-5p inhibited lipid accumulation and oxidative stress injury in ox-LDL-stimulated macrophages. MDM4 was a target gene of miR-34a-5p and was upregulated in ox-LDL-stimulated macrophages. With the increase of ox-LDL treatment and the prolongation of treatment time, the expression level of MDM4 was downregulated. Importantly, MDM4 knockdown partially counteracted the inhibitory effect of miR-34a-5p on oxidative stress injury. CONCLUSION MicroRNA miR-34a-5p knockdown suppressed oxidative stress injury via MDM4 in ox-LDL-treated macrophages.
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Affiliation(s)
- Juan Kong
- Department of Cardiology, The Second Affiliated Hospital of Mudanjiang Medical College, Mudanjiang 157000, Heilongjiang, China
| | - Lei Liu
- Department of Gastroenterology, The Second Affiliated Hospital of Mudanjiang Medical CollegeMudanjiang 157000, Heilongjiang, China
| | - Laixin Song
- Department of Neurosurgery, Second Affiliated Hospital of Mudanjiang Medical University, Changsha 410008, Hunan, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China.,Department of Neurosurgery, The Second Affiliated Hospital of Mudanjiang Medical College,, Mudanjiang 157000, Heilongjiang, China.,Department of Neurosurgery, Department of Surgery, Mudanjiang Huimin Hospital, Mudanjiang157006, Heilongjiang, China
| | - Ruifeng Zhao
- Department of Interventional Therapy, The Second Affiliated Hospital of Mudanjiang Medical College,Mudanjiang 157000, Heilongjiang, China
| | - Ying Feng
- Department of Neurology, The Second Affiliated Hospital of Mudanjiang Medical College, Mudanjiang 157000, Heilongjiang, China
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Bouhamida E, Morciano G, Perrone M, Kahsay AE, Della Sala M, Wieckowski MR, Fiorica F, Pinton P, Giorgi C, Patergnani S. The Interplay of Hypoxia Signaling on Mitochondrial Dysfunction and Inflammation in Cardiovascular Diseases and Cancer: From Molecular Mechanisms to Therapeutic Approaches. BIOLOGY 2022; 11:biology11020300. [PMID: 35205167 PMCID: PMC8869508 DOI: 10.3390/biology11020300] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 02/03/2022] [Accepted: 02/09/2022] [Indexed: 11/16/2022]
Abstract
Simple Summary The regulation of hypoxia has recently emerged as having a central impact in mitochondrial function and dysfunction in various diseases, including the major disorders threatening worldwide: cardiovascular diseases and cancer. Despite the studies in this matter, its effective role in protection and disease progression even though its direct molecular mechanism in both disorders is still to be elucidated. This review aims to cover the current knowledge about the effect of hypoxia on mitochondrial function and dysfunction, and inflammation, in cardiovascular diseases and cancer, and reports further therapeutic strategies based on the modulation of hypoxic pathways. Abstract Cardiovascular diseases (CVDs) and cancer continue to be the primary cause of mortality worldwide and their pathomechanisms are a complex and multifactorial process. Insufficient oxygen availability (hypoxia) plays critical roles in the pathogenesis of both CVDs and cancer diseases, and hypoxia-inducible factor 1 (HIF-1), the main sensor of hypoxia, acts as a central regulator of multiple target genes in the human body. Accumulating evidence demonstrates that mitochondria are the major target of hypoxic injury, the most common source of reactive oxygen species during hypoxia and key elements for inflammation regulation during the development of both CVDs and cancer. Taken together, observations propose that hypoxia, mitochondrial abnormality, oxidative stress, inflammation in CVDs, and cancer are closely linked. Based upon these facts, this review aims to deeply discuss these intimate relationships and to summarize current significant findings corroborating the molecular mechanisms and potential therapies involved in hypoxia and mitochondrial dysfunction in CVDs and cancer.
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Affiliation(s)
- Esmaa Bouhamida
- Department of Medical Sciences and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121 Ferrara, Italy; (E.B.); (G.M.); (M.P.); (A.E.K.); (M.D.S.); (P.P.)
- Translational Research Center, Maria Cecilia Hospital GVM Care & Research, 48022 Cotignola, Italy
| | - Giampaolo Morciano
- Department of Medical Sciences and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121 Ferrara, Italy; (E.B.); (G.M.); (M.P.); (A.E.K.); (M.D.S.); (P.P.)
- Translational Research Center, Maria Cecilia Hospital GVM Care & Research, 48022 Cotignola, Italy
| | - Mariasole Perrone
- Department of Medical Sciences and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121 Ferrara, Italy; (E.B.); (G.M.); (M.P.); (A.E.K.); (M.D.S.); (P.P.)
| | - Asrat E. Kahsay
- Department of Medical Sciences and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121 Ferrara, Italy; (E.B.); (G.M.); (M.P.); (A.E.K.); (M.D.S.); (P.P.)
| | - Mario Della Sala
- Department of Medical Sciences and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121 Ferrara, Italy; (E.B.); (G.M.); (M.P.); (A.E.K.); (M.D.S.); (P.P.)
| | - Mariusz R. Wieckowski
- Laboratory of Mitochondrial Biology and Metabolism, Nencki Institute of Experimental Biology of the Polish Academy of Sciences, 02-093 Warsaw, Poland;
| | - Francesco Fiorica
- Department of Radiation Oncology and Nuclear Medicine, AULSS 9 Scaligera, Ospedale Mater Salutis di Legnago, 37045 Verona, Italy;
| | - Paolo Pinton
- Department of Medical Sciences and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121 Ferrara, Italy; (E.B.); (G.M.); (M.P.); (A.E.K.); (M.D.S.); (P.P.)
- Translational Research Center, Maria Cecilia Hospital GVM Care & Research, 48022 Cotignola, Italy
| | - Carlotta Giorgi
- Department of Medical Sciences and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121 Ferrara, Italy; (E.B.); (G.M.); (M.P.); (A.E.K.); (M.D.S.); (P.P.)
- Correspondence: (C.G.); (S.P.)
| | - Simone Patergnani
- Department of Medical Sciences and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121 Ferrara, Italy; (E.B.); (G.M.); (M.P.); (A.E.K.); (M.D.S.); (P.P.)
- Translational Research Center, Maria Cecilia Hospital GVM Care & Research, 48022 Cotignola, Italy
- Correspondence: (C.G.); (S.P.)
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Bonaterra GA, Struck N, Zuegel S, Schwarz A, Mey L, Schwarzbach H, Strelau J, Kinscherf R. Characterization of atherosclerotic plaques in blood vessels with low oxygenated blood and blood pressure (Pulmonary trunk): role of growth differentiation factor-15 (GDF-15). BMC Cardiovasc Disord 2021; 21:601. [PMID: 34920697 PMCID: PMC8684150 DOI: 10.1186/s12872-021-02420-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 12/09/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Growth differentiation factor (GDF)-15 is linked to inflammation, cancer, and atherosclerosis. GDF-15 is expressed in most tissues but is extremely induced under pathological conditions. Elevated serum levels are suggested as a risk factor and a marker for cardiovascular diseases. However, the cellular sources and the effects of GDF-15 on the cardiovascular system have not been completely elucidated including progression, and morphology of atherosclerotic plaques. Thus, this work aimed to characterize the influence of GDF-15 deficiency on the morphology of atherosclerotic plaques in blood vessels with low-oxygen blood and low blood pressure as the pulmonary trunk (PT), in hypercholesterolemic ApoE-/- mice. METHODS GDF-15-/- ApoE-/- mice were generated by crossbreeding of ApoE-/-- and GDF-15-/- mice. After feeding a cholesterol-enriched diet (CED) for 20 weeks, samples of the brachiocephalic trunk (BT) and PT were dissected and lumen stenosis (LS) was measured. Furthermore, changes in the cellularity of the PT, amounts of apoptosis-, autophagy-, inflammation- and proliferation-relevant proteins were immunohisto-morphometrically analyzed. Additionally, we examined an atherosclerotic plaque in a human post mortem sample of the pulmonary artery. RESULTS After CED the body weight of GDF-15-/-ApoE-/- was 22.9% higher than ApoE-/-. Double knockout mice showed also an 35.3% increase of plasma triglyceride levels, whereas plasma cholesterol was similar in both genotypes. LS in the BT and PT of GDF-15-/-ApoE-/- mice was significantly reduced by 19.0% and by 6.7% compared to ApoE-/-. Comparing LS in PT and BT of the same genotype revealed a significant 38.8% (ApoE-/-) or 26.4% (GDF-15-/-ApoE-/-) lower LS in the PT. Immunohistomorphometry of atherosclerotic lesions in PT of GDF-15-/-ApoE-/- revealed significantly increased levels (39.8% and 7.3%) of CD68 + macrophages (MΦ) and α-actin + smooth muscle cells than in ApoE-/-. The density of TUNEL + , apoptotic cells was significantly (32.9%) higher in plaques of PT of GDF-15-/-ApoE-/- than in ApoE-/-. Analysis of atherosclerotic lesion of a human pulmonary artery showed sm-α-actin, CD68+, TUNEL+, Ki67+, and APG5L/ATG+ cells as observed in PT. COX-2+ and IL-6+ immunoreactivities were predominantly located in endothelial cells and subendothelial space. In BT and PT of GDF15-/-ApoE-/- mice the necrotic area was 10% and 6.5% lower than in ApoE-/-. In BT and PT of GDF15-/-ApoE-/- we found 40% and 57% less unstable plaques than ApoE-/- mice. CONCLUSIONS Atherosclerotic lesions occur in both, BT and PT, however, the size is smaller in PT, possibly due to the effect of the low-oxygen blood and/or lower blood pressure. GDF-15 is involved in atherosclerotic processes in BT and PT, although different mechanisms (e.g. apoptosis) in these two vessels seem to exist.
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Affiliation(s)
- G A Bonaterra
- Institute for Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032, Marburg, Germany.
| | - N Struck
- Institute for Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032, Marburg, Germany
| | - S Zuegel
- Institute for Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032, Marburg, Germany
| | - A Schwarz
- Institute for Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032, Marburg, Germany
| | - L Mey
- Institute for Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032, Marburg, Germany
| | - H Schwarzbach
- Institute for Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032, Marburg, Germany
| | - J Strelau
- Department of Functional Neuroanatomy, University of Heidelberg, 69120, Heidelberg, Germany
| | - R Kinscherf
- Institute for Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032, Marburg, Germany
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Conforti A, Wahlers T, Paunel-Görgülü A. Neutrophil extracellular traps modulate inflammatory markers and uptake of oxidized LDL by human and murine macrophages. PLoS One 2021; 16:e0259894. [PMID: 34797846 PMCID: PMC8604363 DOI: 10.1371/journal.pone.0259894] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 10/29/2021] [Indexed: 01/23/2023] Open
Abstract
Neutrophil extracellular traps (NETs) are web-like structures, which are released upon neutrophil activation. It has previously been demonstrated that NETs are present in atherosclerotic lesions of both humans and animal models thus playing a decisive role in atherosclerosis. Besides, macrophages have a crucial role in disease progression, whereby classically activated M1 macrophages sustain inflammation and alternatively activated M2 macrophages display anti-inflammatory effects. Although NETs and macrophages were found to colocalize in atherosclerotic lesions, the impact of NETs on macrophage function is not fully understood. In the present study, we aimed to investigate the effect of NETs on human and murine macrophages in respect to the expression of pro-inflammatory cytokines, matrix metalloproteinases (MMPs) and uptake of oxidized LDL (oxLDL) in vitro. Human THP-1 and murine bone marrow-derived macrophages were cultured under M1 (LPS + IFN-γ)- and M2a (IL-4)-polarizing culture conditions and treated with NETs. To mimic intraplaque regions, cells were additionally cultured under hypoxic conditions. NETs significantly increased the expression of IL-1β, TNF-α and IL-6 in THP-M1 macrophages under normoxia but suppressed their expression in murine M1 macrophages under hypoxic conditions. Notably, NETs increased the number of oxLDL-positive M1 and M2 human and murine macrophages under normoxia, but did not influence formation of murine foam cells under hypoxia. However, oxLDL uptake did not strongly correlate with the expression of the LDL receptor CD36. Besides, upregulated MMP-9 expression and secretion by macrophages was detected in the presence of NETs. Again, hypoxic culture conditions dampened NETs effects. These results suggest that NETs may favor foam cell formation and plaque vulnerability, but exert opposite effects in respect to the inflammatory response of human and murine M1 macrophages. Moreover, effects of NETs on macrophages’ phenotype are altered under hypoxia.
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Affiliation(s)
- Andreas Conforti
- Department of Cardiothoracic Surgery, Heart Center of The University of Cologne, Cologne, Germany
| | - Thorsten Wahlers
- Department of Cardiothoracic Surgery, Heart Center of The University of Cologne, Cologne, Germany
| | - Adnana Paunel-Görgülü
- Department of Cardiothoracic Surgery, Heart Center of The University of Cologne, Cologne, Germany
- * E-mail:
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Dolfi B, Gallerand A, Haschemi A, Guinamard RR, Ivanov S. Macrophage metabolic regulation in atherosclerotic plaque. Atherosclerosis 2021; 334:1-8. [PMID: 34450556 DOI: 10.1016/j.atherosclerosis.2021.08.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 07/02/2021] [Accepted: 08/05/2021] [Indexed: 12/18/2022]
Abstract
Metabolism plays a key role in controlling immune cell functions. In this review, we will discuss the diversity of plaque resident myeloid cells and will focus on their metabolic demands that could reflect on their particular intraplaque localization. Defining the metabolic configuration of plaque resident myeloid cells according to their topologic distribution could provide answers to key questions regarding their functions and contribution to disease development.
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Affiliation(s)
| | | | - Arvand Haschemi
- Department of Laboratory Medicine, Medical University of Vienna, 1090, Vienna, Austria
| | - Rodolphe R Guinamard
- Université Côte D'Azur, Laboratoire de PhysioMédecine Moléculaire, CNRS, Nice, France
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Knutson AK, Williams AL, Boisvert WA, Shohet RV. HIF in the heart: development, metabolism, ischemia, and atherosclerosis. J Clin Invest 2021; 131:137557. [PMID: 34623330 DOI: 10.1172/jci137557] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The heart forms early in development and delivers oxygenated blood to the rest of the embryo. After birth, the heart requires kilograms of ATP each day to support contractility for the circulation. Cardiac metabolism is omnivorous, utilizing multiple substrates and metabolic pathways to produce this energy. Cardiac development, metabolic tuning, and the response to ischemia are all regulated in part by the hypoxia-inducible factors (HIFs), central components of essential signaling pathways that respond to hypoxia. Here we review the actions of HIF1, HIF2, and HIF3 in the heart, from their roles in development and metabolism to their activity in regeneration and preconditioning strategies. We also discuss recent work on the role of HIFs in atherosclerosis, the precipitating cause of myocardial ischemia and the leading cause of death in the developed world.
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Dietz M, Kamani CH, Deshayes E, Dunet V, Mitsakis P, Coukos G, Nicod Lalonde M, Schaefer N, Prior JO. Imaging angiogenesis in atherosclerosis in large arteries with 68Ga-NODAGA-RGD PET/CT: relationship with clinical atherosclerotic cardiovascular disease. EJNMMI Res 2021; 11:71. [PMID: 34390409 PMCID: PMC8364589 DOI: 10.1186/s13550-021-00815-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Accepted: 07/14/2021] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND Integrin alpha-V-beta-3 (αvβ3) pathway is involved in intraplaque angiogenesis and inflammation and represents a promising target for molecular imaging in cardiovascular diseases such as atherosclerosis. The aim of this study was to assess the clinical correlates of arterial wall accumulation of 68Ga-NODAGA-RGD, a specific αvβ3 integrin ligand for PET. MATERIALS AND METHODS The data of 44 patients who underwent 68Ga-NODAGA-RGD PET/CT scans were retrospectively analyzed. Tracer accumulation in the vessel wall of major arteries was analyzed semi-quantitatively by blood-pool-corrected target-to-background ratios. Tracer uptake was compared with clinically documented atherosclerotic cardiovascular disease, cardiovascular risk factors and calcified plaque burden. Data were compared using the Mann-Whitney U test, Pearson correlation and Spearman correlation. RESULTS 68Ga-NODAGA-RGD arterial uptake was significantly higher in patients with previous clinically documented atherosclerotic cardiovascular disease (mean TBR 2.44 [2.03-2.55] vs. 1.81 [1.56-1.96], p = 0.001) and showed a significant correlation with prior cardiovascular or cerebrovascular event (r = 0.33, p = 0.027), BMI (ρ = 0.38, p = 0.01), plaque burden (ρ = 0.31, p = 0.04) and hypercholesterolemia (r = 0.31, p = 0.04). CONCLUSIONS 68Ga-NODAGA-RGD holds promise as a non-invasive marker of disease activity in atherosclerosis, providing information about intraplaque angiogenesis.
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Affiliation(s)
- Matthieu Dietz
- Nuclear Medicine and Molecular Imaging Department, Lausanne University Hospital, Rue du Bugnon 46, 1011, Lausanne, Switzerland
| | - Christel H Kamani
- Nuclear Medicine and Molecular Imaging Department, Lausanne University Hospital, Rue du Bugnon 46, 1011, Lausanne, Switzerland
| | - Emmanuel Deshayes
- Nuclear Medicine Department, Montpellier Cancer Institute (ICM), University of Montpellier, 208 Avenue des Apothicaires, 34298, Montpellier Cedex 5, France
| | - Vincent Dunet
- Department of Diagnostic and Interventional Radiology, Lausanne University Hospital, Rue du Bugnon 46, 1011, Lausanne, Switzerland
| | - Periklis Mitsakis
- Nuclear Medicine and Molecular Imaging Department, Lausanne University Hospital, Rue du Bugnon 46, 1011, Lausanne, Switzerland
| | - George Coukos
- Ludwig Institute for Cancer Research and Department of Oncology, Lausanne University Hospital, Rue du Bugnon 46, 1011, Lausanne, Switzerland
| | - Marie Nicod Lalonde
- Nuclear Medicine and Molecular Imaging Department, Lausanne University Hospital, Rue du Bugnon 46, 1011, Lausanne, Switzerland
| | - Niklaus Schaefer
- Nuclear Medicine and Molecular Imaging Department, Lausanne University Hospital, Rue du Bugnon 46, 1011, Lausanne, Switzerland
| | - John O Prior
- Nuclear Medicine and Molecular Imaging Department, Lausanne University Hospital, Rue du Bugnon 46, 1011, Lausanne, Switzerland.
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Liang S, Ning R, Zhang J, Liu J, Zhang J, Shen H, Chen R, Duan J, Sun Z. MiR-939-5p suppresses PM 2.5-induced endothelial injury via targeting HIF-1α in HAECs. Nanotoxicology 2021; 15:706-720. [PMID: 33941019 DOI: 10.1080/17435390.2021.1917716] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Ambient air pollution is a leading cause of non-communicable disease in the world. PM2.5 has the potential to change the miRNAs profiles, which in turn causes cardiovascular effects. Hypoxia-inducible factor (HIF)-1 plays a critical role in the development of atherosclerosis. Yet, the possible role of miR-939-5p/HIF-1α in PM2.5-induced endothelial injury remains elusive. Therefore, the study aims to investigate the effects of miR-939-5p and HIF-1α on PM2.5-triggered endothelial injury. The results from immunofluorescence, qRT-PCR, LSCM, and western blot assays demonstrated that PM2.5 increased the levels of HIF-1α, inflammation and apoptosis in human aortic endothelial cells (HAECs). Yet, the inflammatory response and mitochondrial-mediated apoptosis pathway were effectively inhibited in HIF-1α knockdown HAECs lines. The expression of miR-939-5p was significantly down-regulated in HAECs after exposed to PM2.5. The luciferase reporter, qRT-PCR and western blot results demonstrated that miR-939-5p could directly targeted HIF-1α. And the miR-939-5p overexpression restricted PM2.5-triggered decreases in cell viability and increases in lactic dehydrogenase (LDH) activity, reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and inflammation. In addition, miR-939-5p overexpression remarkably suppressed PM2.5-triggered BcL-2/Bax ratio reduction and Cytochrome C, Cleaved Caspase-9 and Cleaved Caspase-3 expression increase, revealed that miR-939-5p hampered PM2.5-induced endothelial apoptosis through mitochondrial-mediated apoptosis pathway. Our results demonstrated that PM2.5 increased the expression of HIF-1α followed by a pro-inflammatory and apoptotic response in HAECs. The protective effect of miR-939-5p on PM2.5-triggered endothelial cell injury by negatively regulating HIF-1α. miR-939-5p might present a new therapeutic target for PM2.5 induced endothelial injury.
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Affiliation(s)
- Shuang Liang
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, PR China.,Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, PR China
| | - Ruihong Ning
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, PR China.,Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, PR China
| | - Jingyi Zhang
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, PR China.,Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, PR China
| | - Jiangyan Liu
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, PR China.,Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, PR China
| | - Jie Zhang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, PR China
| | - Heqing Shen
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, PR China.,Key Laboratory of Urban Environment and Health, Chinese Academy of Sciences, Institute of Urban Environment, Xiamen, PR China
| | - Rui Chen
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, PR China.,Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, PR China
| | - Junchao Duan
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, PR China.,Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, PR China
| | - Zhiwei Sun
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, PR China.,Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, PR China
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Sluiter TJ, van Buul JD, Huveneers S, Quax PHA, de Vries MR. Endothelial Barrier Function and Leukocyte Transmigration in Atherosclerosis. Biomedicines 2021; 9:328. [PMID: 33804952 PMCID: PMC8063931 DOI: 10.3390/biomedicines9040328] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Revised: 03/17/2021] [Accepted: 03/19/2021] [Indexed: 12/24/2022] Open
Abstract
The vascular endothelium is a highly specialized barrier that controls passage of fluids and migration of cells from the lumen into the vessel wall. Endothelial cells assist leukocytes to extravasate and despite the variety in the specific mechanisms utilized by different leukocytes to cross different vascular beds, there is a general principle of capture, rolling, slow rolling, arrest, crawling, and ultimately diapedesis via a paracellular or transcellular route. In atherosclerosis, the barrier function of the endothelium is impaired leading to uncontrolled leukocyte extravasation and vascular leakage. This is also observed in the neovessels that grow into the atherosclerotic plaque leading to intraplaque hemorrhage and plaque destabilization. This review focuses on the vascular endothelial barrier function and the interaction between endothelial cells and leukocytes during transmigration. We will discuss the role of endothelial dysfunction, transendothelial migration of leukocytes and plaque angiogenesis in atherosclerosis.
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Affiliation(s)
- Thijs J. Sluiter
- Department of Vascular Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (T.J.S.); (P.H.A.Q.)
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| | - Jaap D. van Buul
- Sanquin Research and Landsteiner Laboratory, Leeuwenhoek Centre for Advanced Microscopy, Swammerdam Institute for Life Sciences, University of Amsterdam, 1066 CX Amsterdam, The Netherlands;
| | - Stephan Huveneers
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Center, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
| | - Paul H. A. Quax
- Department of Vascular Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (T.J.S.); (P.H.A.Q.)
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| | - Margreet R. de Vries
- Department of Vascular Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (T.J.S.); (P.H.A.Q.)
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
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Regulatory T Cell Stability and Plasticity in Atherosclerosis. Cells 2020; 9:cells9122665. [PMID: 33322482 PMCID: PMC7764358 DOI: 10.3390/cells9122665] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 12/08/2020] [Accepted: 12/08/2020] [Indexed: 12/17/2022] Open
Abstract
Regulatory T cells (Tregs) express the lineage-defining transcription factor FoxP3 and play crucial roles in self-tolerance and immune homeostasis. Thymic tTregs are selected based on affinity for self-antigens and are stable under most conditions. Peripheral pTregs differentiate from conventional CD4 T cells under the influence of TGF-β and other cytokines and are less stable. Treg plasticity refers to their ability to inducibly express molecules characteristic of helper CD4 T cell lineages like T-helper (Th)1, Th2, Th17 or follicular helper T cells. Plastic Tregs retain FoxP3 and are thought to be specialized regulators for “their” lineage. Unstable Tregs lose FoxP3 and switch to become exTregs, which acquire pro-inflammatory T-helper cell programs. Atherosclerosis with systemic hyperlipidemia, hypercholesterolemia, inflammatory cytokines, and local hypoxia provides an environment that is likely conducive to Tregs switching to exTregs.
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Abstract
Abstract
Purpose
Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) positron emission tomography (CuATSM PET) is a non-invasive imaging technique that can be used to detect hypoxia and inform prognosis in cancer. Hypoxia and oxidative stress are also hallmarks of various age-related diseases. Whether CuATSM PET has a role in the evaluation of hypoxia and oxidative stress in age-related diseases has yet to be established. The aim of this systematic review is to evaluate the utility of CuATSM PET in the diagnosis and management of age-related diseases.
Methods
EMBASE, Medline, Scopus, Web of Science and Psychinfo were systematically searched for articles published between January 1st 1997 and February 13th 2020. We included articles published in English reporting the use of CuATSM PET in the diagnosis and management of age-related diseases in humans or animals.
Results
Nine articles were included describing CuATSM PET measures in neurological and cardiovascular disease. There was higher CuATSM uptake in diseased compared to control subjects in Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), myocardial ischemia (MI), cardiac dysautonomia and atherosclerosis. Higher CuATSM uptake was seen in diseased compared to control anatomical areas in PD, cerebrovascular disease (CVD), MI and atherosclerosis. CuATSM uptake was associated with disease severity in PD, ALS, CVD and atherosclerosis. An association between CuATSM uptake and disease duration was shown in atherosclerosis.
Conclusion
CuATSM uptake is higher in neurological and cardiovascular diseases and associated with disease severity and duration. Further investigations using CuATSM PET in other age-related diseases are needed.
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Gallerand A, Stunault MI, Merlin J, Guinamard RR, Yvan-Charvet L, Ivanov S. Myeloid Cell Diversity and Impact of Metabolic Cues during Atherosclerosis. IMMUNOMETABOLISM 2020; 2:immunometab20200028. [PMID: 39649554 PMCID: PMC7617020 DOI: 10.20900/immunometab20200028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/11/2024]
Abstract
Myeloid cells are key contributors to tissue, immune and metabolic homeostasis and their alteration fuels inflammation and associated disorders such as atherosclerosis. Conversely, in a classical chicken-and-egg situation, systemic and local metabolism, together with receptor-mediated activation, regulate intracellular metabolism and reprogram myeloid cell functions. Those regulatory loops are notable during the development of atherosclerotic lesions. Therefore, understanding the intricate metabolic mechanisms regulating myeloid cell biology could lead to innovative approaches to prevent and treat cardiovascular diseases. In this review, we will attempt to summarize the different metabolic factors regulating myeloid cell homeostasis and contribution to atherosclerosis, the most frequent cardiovascular disease.
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Affiliation(s)
- Alexandre Gallerand
- Mediterranean center of molecular medicine (C3M)-Université Côte d’Azur–INSERM U1065, Team 13, Nice, 06200, France
| | - Marion I. Stunault
- Mediterranean center of molecular medicine (C3M)-Université Côte d’Azur–INSERM U1065, Team 13, Nice, 06200, France
| | - Johanna Merlin
- Mediterranean center of molecular medicine (C3M)-Université Côte d’Azur–INSERM U1065, Team 13, Nice, 06200, France
| | - Rodolphe R. Guinamard
- Mediterranean center of molecular medicine (C3M)-Université Côte d’Azur–INSERM U1065, Team 13, Nice, 06200, France
| | - Laurent Yvan-Charvet
- Mediterranean center of molecular medicine (C3M)-Université Côte d’Azur–INSERM U1065, Team 13, Nice, 06200, France
| | - Stoyan Ivanov
- Mediterranean center of molecular medicine (C3M)-Université Côte d’Azur–INSERM U1065, Team 13, Nice, 06200, France
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Stitham J, Rodriguez-Velez A, Zhang X, Jeong SJ, Razani B. Inflammasomes: a preclinical assessment of targeting in atherosclerosis. Expert Opin Ther Targets 2020; 24:825-844. [PMID: 32757967 PMCID: PMC7554266 DOI: 10.1080/14728222.2020.1795831] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Accepted: 07/12/2020] [Indexed: 01/07/2023]
Abstract
INTRODUCTION Inflammasomes are central to atherosclerotic vascular dysfunction with regulatory effects on inflammation, immune modulation, and lipid metabolism. The NLRP3 inflammasome is a critical catalyst for atherogenesis thus highlighting its importance in understanding the pathophysiology of atherosclerosis and for the identification of novel therapeutic targets and biomarkers for the treatment of cardiovascular disease. AREAS COVERED This review includes an overview of macrophage lipid metabolism and the role of NLRP3 inflammasome activity in cardiovascular inflammation and atherosclerosis. We highlight key activators, signal transducers and major regulatory components that are being considered as putative therapeutic targets for inhibition of NLRP3-mediated cardiovascular inflammation and atherosclerosis. EXPERT OPINION NLRP3 inflammasome activity lies at the nexus between inflammation and cholesterol metabolism; it offers unique opportunities for understanding atherosclerotic pathophysiology and identifying novel modes of treatment. As such, a host of NLRP3 signaling cascade components have been identified as putative targets for drug development. We catalog these current discoveries in therapeutic targeting of the NLRP3 inflammasome and, utilizing the CANTOS trial as the translational (bench-to-bedside) archetype, we examine the complexities, challenges, and ultimate goals facing the field of atherosclerosis research.
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Affiliation(s)
- Jeremiah Stitham
- Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO
| | - Astrid Rodriguez-Velez
- Department of Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO
| | - Xiangyu Zhang
- Department of Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO
- John Cochran VA Medical Center, St. Louis, MO
| | - Se-Jin Jeong
- Department of Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO
- John Cochran VA Medical Center, St. Louis, MO
| | - Babak Razani
- Department of Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO
- Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO
- John Cochran VA Medical Center, St. Louis, MO
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45
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Lightbody RJ, Taylor JMW, Dempsie Y, Graham A. MicroRNA sequences modulating inflammation and lipid accumulation in macrophage “foam” cells: Implications for atherosclerosis. World J Cardiol 2020; 12:303-333. [PMID: 32843934 PMCID: PMC7415235 DOI: 10.4330/wjc.v12.i7.303] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 06/03/2020] [Accepted: 06/10/2020] [Indexed: 02/06/2023] Open
Abstract
Accumulation of macrophage “foam” cells, laden with cholesterol and cholesteryl ester, within the intima of large arteries, is a hallmark of early “fatty streak” lesions which can progress to complex, multicellular atheromatous plaques, involving lipoproteins from the bloodstream and cells of the innate and adaptive immune response. Sterol accumulation triggers induction of genes encoding proteins mediating the atheroprotective cholesterol efflux pathway. Within the arterial intima, however, this mechanism is overwhelmed, leading to distinct changes in macrophage phenotype and inflammatory status. Over the last decade marked gains have been made in understanding of the epigenetic landscape which influence macrophage function, and in particular the importance of small non-coding micro-RNA (miRNA) sequences in this context. This review identifies some of the miRNA sequences which play a key role in regulating “foam” cell formation and atherogenesis, highlighting sequences involved in cholesterol accumulation, those influencing inflammation in sterol-loaded cells, and novel sequences and pathways which may offer new strategies to influence macrophage function within atherosclerotic lesions.
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Affiliation(s)
- Richard James Lightbody
- Department of Biological and Biomedical Sciences, School of Health and Life Sciences, Glasgow Caledonian University, Glasgow G4 0BA, United Kingdom
| | - Janice Marie Walsh Taylor
- Department of Biological and Biomedical Sciences, School of Health and Life Sciences, Glasgow Caledonian University, Glasgow G4 0BA, United Kingdom
| | - Yvonne Dempsie
- Department of Biological and Biomedical Sciences, School of Health and Life Sciences, Glasgow Caledonian University, Glasgow G4 0BA, United Kingdom
| | - Annette Graham
- Department of Biological and Biomedical Sciences, School of Health and Life Sciences, Glasgow Caledonian University, Glasgow G4 0BA, United Kingdom
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46
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Wang Q, Wu J, Zeng Y, Chen K, Wang C, Yang S, Sun N, Chen H, Duan K, Zeng G. Pyroptosis: A pro-inflammatory type of cell death in cardiovascular disease. Clin Chim Acta 2020; 510:62-72. [PMID: 32622968 DOI: 10.1016/j.cca.2020.06.044] [Citation(s) in RCA: 124] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 06/19/2020] [Accepted: 06/26/2020] [Indexed: 01/12/2023]
Abstract
Pyroptosis is a pro-inflammatory type of regulated cell death (RCD) characterized by gasdermin D (GSDMD)-mediated membrane pore formation, cell swelling and rapid lysis, followed by the massive release of pro-inflammatory mediators such as interleukin-1β and interleukin-18. There are two main pathways of pyroptosis: the caspase-1-mediated canonical pathway and the caspase-4/5/11-mediated noncanonical pathway. However, the caspase-3-gasdermin E (GSDME) pathway and caspase-8-GSDMD pathway also induce pyroptosis. Pyroptosis can not only cause local inflammation but also lead to amplification of the inflammatory response. Recent studies have suggested that pyroptosis is closely related with cardiovascular disease (CVD); for example, in atherosclerosis, myocardial infarction, ischemia-reperfusion injury, heart failure, coronary calcification and aortic aneurysm, study results have promoted the development of inhibitors targeting the components related to pyroptosis, and some agents have been clinically proven to have cardiovascular benefits. In this review, we summarize emerging evidence to discuss the progressive understanding of pyroptosis and the pathways, effect and effectors of pyroptosis, as well as the role of pyroptosis in CVD. Additionally, we summarize pyroptosis-related pathway inhibitors and classic cardiovascular drugs targeting pyroptosis.
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Affiliation(s)
- Qun Wang
- Department of Cardiovascular Medicine, Key Laboratory of Heart Failure Prevention & Treatment of Hengyang, the Second Affiliated Hospital of University of South China, 421001 Hunan Province, China
| | - Jianfeng Wu
- Department of Cardiovascular Medicine, Key Laboratory of Heart Failure Prevention & Treatment of Hengyang, the Second Affiliated Hospital of University of South China, 421001 Hunan Province, China
| | - Yicheng Zeng
- Hengyang Medical College, University of South China, 421001 Hunan Province, China
| | - Kong Chen
- Department of Cardiovascular Medicine, Key Laboratory of Heart Failure Prevention & Treatment of Hengyang, the Second Affiliated Hospital of University of South China, 421001 Hunan Province, China
| | - Chuangxin Wang
- Department of Cardiovascular Medicine, Key Laboratory of Heart Failure Prevention & Treatment of Hengyang, the Second Affiliated Hospital of University of South China, 421001 Hunan Province, China
| | - Shiqi Yang
- Department of Cardiovascular Medicine, Key Laboratory of Heart Failure Prevention & Treatment of Hengyang, the Second Affiliated Hospital of University of South China, 421001 Hunan Province, China
| | - Nisi Sun
- Department of Cardiovascular Medicine, Key Laboratory of Heart Failure Prevention & Treatment of Hengyang, the Second Affiliated Hospital of University of South China, 421001 Hunan Province, China
| | - Hao Chen
- Department of Cardiovascular Medicine, Key Laboratory of Heart Failure Prevention & Treatment of Hengyang, the Second Affiliated Hospital of University of South China, 421001 Hunan Province, China
| | - Kang Duan
- Department of Cardiovascular Medicine, Key Laboratory of Heart Failure Prevention & Treatment of Hengyang, the Second Affiliated Hospital of University of South China, 421001 Hunan Province, China
| | - Gaofeng Zeng
- Department of Cardiovascular Medicine, Key Laboratory of Heart Failure Prevention & Treatment of Hengyang, the Second Affiliated Hospital of University of South China, 421001 Hunan Province, China.
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van Tuijl J, Joosten LAB, Netea MG, Bekkering S, Riksen NP. Immunometabolism orchestrates training of innate immunity in atherosclerosis. Cardiovasc Res 2020; 115:1416-1424. [PMID: 31050710 PMCID: PMC6910162 DOI: 10.1093/cvr/cvz107] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2018] [Revised: 02/14/2019] [Accepted: 04/25/2019] [Indexed: 12/11/2022] Open
Abstract
Atherosclerosis is characterized by a persistent, low-grade inflammation of the arterial wall. Monocytes and monocyte-derived macrophages play a pivotal role in the various stages of atherosclerosis. In the past few years, metabolic reprogramming has been identified as an important controller of myeloid cell activation status. In addition, metabolic and epigenetic reprogramming are key regulatory mechanisms of trained immunity, which denotes the non-specific innate immune memory that can develop after brief stimulation of monocytes with microbial or non-microbial stimuli. In this review, we build the case that metabolic reprogramming of monocytes and macrophages, and trained immunity in particular, contribute to the pathophysiology of atherosclerosis. We discuss the specific metabolic adaptations, including changes in glycolysis, oxidative phosphorylation, and cholesterol metabolism, that have been reported in atherogenic milieus in vitro and in vivo. In addition, we will focus on the role of these metabolic pathways in the development of trained immunity.
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Affiliation(s)
- Julia van Tuijl
- Department of Internal Medicine, Radboud University Medical Center Nijmegen, Geert Grooteplein Zuid 8, GA, HB Nijmegen, The Netherlands
| | - Leo A B Joosten
- Department of Internal Medicine, Radboud University Medical Center Nijmegen, Geert Grooteplein Zuid 8, GA, HB Nijmegen, The Netherlands.,Department of Medical Genetics, Iuliu Hatieganu University of Medicine and Pharmacy, Str. Pasteur 6, Cluj-Napoca, Romania
| | - Mihai G Netea
- Department of Internal Medicine, Radboud University Medical Center Nijmegen, Geert Grooteplein Zuid 8, GA, HB Nijmegen, The Netherlands.,Department for Genomics & Immunoregulation, Life and Sciences Institute (LIMES), University of Bonn, Carl-Troll-Straβe 31, Bonn, Germany
| | - Siroon Bekkering
- Department of Internal Medicine, Radboud University Medical Center Nijmegen, Geert Grooteplein Zuid 8, GA, HB Nijmegen, The Netherlands
| | - Niels P Riksen
- Department of Internal Medicine, Radboud University Medical Center Nijmegen, Geert Grooteplein Zuid 8, GA, HB Nijmegen, The Netherlands
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Umbro I, Fabiani V, Fabiani M, Angelico F, Del Ben M. Association between non-alcoholic fatty liver disease and obstructive sleep apnea. World J Gastroenterol 2020; 26:2669-2681. [PMID: 32523319 PMCID: PMC7265151 DOI: 10.3748/wjg.v26.i20.2669] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 03/26/2020] [Accepted: 05/15/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is an emerging liver disease and currently the most common cause of incidental abnormal liver tests. The pathogenesis of NAFLD is multifactorial and many mechanisms that cause fatty liver infiltration, inflammation, oxidative stress and progressive fibrosis have been proposed. Obstructive sleep apnea (OSA) may be linked with the pathogenesis and the severity of NAFLD. AIM To study the association between NAFLD and OSA considering also the efficacy of continuous positive airway pressure (CPAP) treatment. METHODS A PubMed search was conducted using the terms "non-alcoholic fatty liver disease AND (obstructive sleep apnea OR obstructive sleep disorders OR sleep apnea)". Research was limited to title/abstract of articles published in English in the last 5 years; animal and child studies, case reports, commentaries, letters, editorials and meeting abstracts were not considered. Data were extracted on a standardized data collection table which included: First author, publication year, country, study design, number of patients involved, diagnosis and severity of OSA, diagnosis of NAFLD, patient characteristics, results of the study. RESULTS In total, 132 articles were initially retrieved on PubMed search and 77 in the last five years. After removal of irrelevant studies, 13 articles were included in the qualitative analysis. There was a total of 2753 participants across all the studies with a mean age between 42 and 58 years. The proportion of males ranged from 21% to 87.9% and the mean body mass index ranged from 24.0 to 49.9 kg/m2. The results of this review showed an increased prevalence of NAFLD in patients with diagnosis of OSA, even in the absence of coexisting comorbidities such as obesity or metabolic syndrome. Furthermore, the severity of NAFLD is associated with the increase in OSA severity. Effective CPAP treatment, although not always decisive, may stabilize or slow NAFLD progression with benefits on metabolic and cardiovascular functions. CONCLUSION In NAFLD patients, although asymptomatic, it is recommended to systematically perform polysomnography in order to early and better treat them before the development of potentially life threatening systemic dysfunctions.
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Affiliation(s)
- Ilaria Umbro
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome 00161, Italy
| | - Valerio Fabiani
- Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University of Rome, Rome 00123, Italy
| | - Mario Fabiani
- Department of Sense Organs, Sapienza University of Rome, Rome 00161, Italy
| | - Francesco Angelico
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome 00161, Italy
| | - Maria Del Ben
- Department of Clinical, Internal, Anesthetic and Cardiovascular Sciences, Sapienza University of Rome, Rome 00161, Italy
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50
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Ménégaut L, Thomas C, Jalil A, Julla JB, Magnani C, Ceroi A, Basmaciyan L, Dumont A, Le Goff W, Mathew MJ, Rébé C, Dérangère V, Laubriet A, Crespy V, Pais de Barros JP, Steinmetz E, Venteclef N, Saas P, Lagrost L, Masson D. Interplay between Liver X Receptor and Hypoxia Inducible Factor 1α Potentiates Interleukin-1β Production in Human Macrophages. Cell Rep 2020; 31:107665. [DOI: 10.1016/j.celrep.2020.107665] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Revised: 01/09/2020] [Accepted: 04/28/2020] [Indexed: 11/16/2022] Open
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