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Yu W, Fu L, Lei G, Luo F, Yu P, Shen W, Wu Q, Yang P. Chemokine Ligands and Receptors Regulate Macrophage Polarization in Atherosclerosis: A Comprehensive Database Mining Study. CJC Open 2025; 7:310-324. [PMID: 40182401 PMCID: PMC11963153 DOI: 10.1016/j.cjco.2024.11.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Accepted: 11/18/2024] [Indexed: 04/05/2025] Open
Abstract
Background Atherosclerosis is a systemic disease involving multiple blood vessels and a major cause of cardiovascular disease. Current treatment methods (eg, statins) for atherosclerosis can reduce the risk of cardiovascular diseases effectively, but they are insufficient to completely reverse existing atherosclerosis. Macrophages play a central role in development of atherosclerosis. Chemokines, the main mediators of macrophage chemotaxis, are important in immune and inflammatory responses. The effects of chemokines on mechanisms involved in atherosclerosis are unknown. This study preliminarily investigated these effects and mechanisms via bioinformatics methods. Methods In this study, data on chemokine ligands and receptors were obtained by mining public databases (the National Center of Biotechnology Information-Gene Expression Omnibus [NCBI-GEO] database, ArrayExpress database, and single-cell RNA sequencing [scRNA-seq] database), and an extensive literature search was performed. The expression levels of chemokines in mouse tissues were analyzed via Metascape software for signalling pathway enrichment, scRNA-seq data for chemokine expression in atherosclerotic plaque progression and regression, and GEO2R data for chemokine expression during macrophage polarization. Ingenuity Pathway Analysis (IPA) software was used to analyze regulatory factors such as transcription factors and microRNAs that are significantly differentially expressed upstream of chemokines in macrophage polarization. Finally, a model of the chemokine regulation of atherosclerosis was established on the basis of these results. Results There are 5 main findings: (1) In atherosclerosis, chemokines are regulated by transcription factors and microRNAs. (2) The transcription factor STAT1 promotes the polarization of dormant (M0) macrophages into classically activated (M1) macrophages and alternative activated (M2) macrophages by regulating chemokines. The transcription factors STAT1, IRF7 and IRF1 regulate the polarization of M0 macrophages into M2a and M2b macrophages via different chemokines. For example, some transcription factors promote M1 polarization of M0 macrophages through CCL4, but M2 macrophage polarization is regulated via CCL19, CCL5 and CCR7. (3) Transcription factors can promote and inhibit, whereas miRNAs can only inhibit atherosclerosis. (4) CCL4 existed in all 5 different chemokine-regulated macrophage models, whereas CXCL3 only existed in the M2b macrophage transcriptional regulation model, indicating that CXCL3 may promote the M2b type macrophages polarization of M0 macrophages. (5) CCL5 and CCR7 can promote the M2a macrophages and M2b macrophages polarization of M0 macrophages. Conclusions Atherosclerosis can be treated by regulating chemokines and regulating the polarization of macrophages. The chemokines CCL4, CCL5, CCL8, CCL19, CXCL3, CXCL10, CXCL13, and CCR7 may play key roles in the progression and regression of atherosclerosis.
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Affiliation(s)
- Wanqian Yu
- Department of Cardiovascular Medicine, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Linghua Fu
- Department of Cardiovascular Medicine, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Guangtao Lei
- Department of Cardiovascular Medicine, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Fan Luo
- Department of Gastroenterology, Jiangxi Provincial Hospital of Traditional Chinese Medicine, Nanchang, Jiangxi, China
| | - Peng Yu
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Wen Shen
- Department of Cardiovascular Medicine, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Qinghua Wu
- Department of Cardiovascular Medicine, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Pingping Yang
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
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Gao S, Chen H. Therapeutic potential of apelin and Elabela in cardiovascular disease. Biomed Pharmacother 2023; 166:115268. [PMID: 37562237 DOI: 10.1016/j.biopha.2023.115268] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 07/28/2023] [Accepted: 07/31/2023] [Indexed: 08/12/2023] Open
Abstract
Apelin and Elabela (Ela) are peptides encoded by APLN and APELA, respectively, which act on their receptor APJ and play crucial roles in the body. Recent research has shown that they not only have important effects on the endocrine system, but also promote vascular development and maintain the homeostasis of myocardial cells. From a molecular biology perspective, we explored the roles of Ela and apelin in the cardiovascular system and summarized the mechanisms of apelin-APJ signaling in the progression of myocardial infarction, ischemia-reperfusion injury, atherosclerosis, pulmonary arterial hypertension, preeclampsia, and congenital heart disease. Evidences indicated that apelin and Ela play important roles in cardiovascular diseases, and there are many studies focused on developing apelin, Ela, and their analogues for clinical treatments. However, the literature on the therapeutic potential of apelin, Ela and their analogues and other APJ agonists in the cardiovascular system is still limited. This review summarized the regulatory pathways of apelin/ELA-APJ axis in cardiovascular function and cardiovascular-related diseases, and the therapeutic effects of their analogues in cardiovascular diseases were also included.
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Affiliation(s)
- Shenghan Gao
- Department of Histology and embryology, Medical College of Nanchang University, Nanchang, Jiangxi 330006, PR China; Queen Mary School, Medical Department, Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Hongping Chen
- Department of Histology and embryology, Medical College of Nanchang University, Nanchang, Jiangxi 330006, PR China.
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Wang X, Zhang L, Li P, Zheng Y, Yang Y, Ji S. Apelin/APJ system in inflammation. Int Immunopharmacol 2022; 109:108822. [DOI: 10.1016/j.intimp.2022.108822] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 04/23/2022] [Accepted: 04/29/2022] [Indexed: 12/18/2022]
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You D, Qiao Q, Ono K, Wei M, Tan W, Wang C, Liu Y, Liu G, Zheng M. miR-223-3p inhibits the progression of atherosclerosis via down-regulating the activation of MEK1/ERK1/2 in macrophages. Aging (Albany NY) 2022; 14:1865-1878. [PMID: 35202001 PMCID: PMC8908932 DOI: 10.18632/aging.203908] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 01/11/2022] [Indexed: 06/07/2023]
Abstract
BACKGROUND microRNAs (miRNAs) have drawn more attention to the progression of atherosclerosis (AS), due to their noticeable inflammation function in cardiovascular disease. Macrophages play a crucial role in disrupting atherosclerotic plaque, thereby we explored the involvement of miR-223-3p in the inflammatory response in macrophages. METHODS RT-qPCR was used to analyze the miR-223-3p levels in carotid arteries and serum of AS patients. ROC curve was used to assess the diagnostic value of miR-223-3p. Movat staining was applied to evaluate the morphological differences. FISH was used to identify the expression of miR-223-3p in macrophages of atherosclerotic lesions. Bioinformatic analysis was performed. Double-immunofluorescence and western blot were performed to assess the inflammatory cytokine secretion and p-ERK1/2. C16-PAF was injected into the culture medium of the miR-223-3p mimic/NC-transfected macrophages with ox-LDL. RESULTS MiR-223-3p was up-regulated in AS patients and was associated with a higher overall survival rate. MiR-223-3p was co-localized with CD68+ macrophages in vulnerable atherosclerotic lesions. MiR-223-3p mimics decreased atherosclerotic lesions, macrophages numbers whereas increased SMCs numbers in the lesions. The TNF-a immune-positive areas were reduced by miR-223-3p mimics. MAP2K1 was negatively associated with miR-223-3p. MiR-223-3p mimics reduced the inflammation and the MEK1/ERK1/2 signaling pathway in vivo and in vitro. C16-PAF reversed the effects of miR-223-3p mimics on inflammation and ERK1/2 signaling pathway. CONCLUSIONS MiR-223-3p negatively regulates inflammatory responses by the MEK1/ERK1/2 signaling pathway. Our study provides new insight into how miR-223-3p protects against atherosclerosis, representing a broader therapeutic prospect for treating atherosclerosis by miR-223-3p.
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Affiliation(s)
- Daofeng You
- Hebei Medical University First Affiliated Hospital, Shijiazhuang 050023, Hebei, China
| | - Qiuge Qiao
- Hebei Medical University Second Affiliated Hospital, Shijiazhuang 050023, Hebei, China
| | - Katsushige Ono
- Department of Pathophysiology, Oita University School of Medicine, Hasama, Yufu, Ōita-shi, Japan
| | - Mei Wei
- Hebei Medical University First Affiliated Hospital, Shijiazhuang 050023, Hebei, China
| | - Wenyun Tan
- Hebei Medical University First Affiliated Hospital, Shijiazhuang 050023, Hebei, China
| | - Cuihua Wang
- Hebei Medical University First Affiliated Hospital, Shijiazhuang 050023, Hebei, China
| | - Yangong Liu
- Hebei Medical University First Affiliated Hospital, Shijiazhuang 050023, Hebei, China
| | - Gang Liu
- Hebei Medical University First Affiliated Hospital, Shijiazhuang 050023, Hebei, China
| | - Mingqi Zheng
- Hebei Medical University First Affiliated Hospital, Shijiazhuang 050023, Hebei, China
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Sakamoto S, Mallah D, Medeiros DJ, Dohi E, Imai T, Rose IVL, Matoba K, Zhu X, Kamiya A, Kano SI. Alterations in circulating extracellular vesicles underlie social stress-induced behaviors in mice. FEBS Open Bio 2021; 11:2678-2692. [PMID: 34043886 PMCID: PMC8487053 DOI: 10.1002/2211-5463.13204] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Revised: 05/04/2021] [Accepted: 05/25/2021] [Indexed: 11/17/2022] Open
Abstract
Chronic stress induces peripheral and intracerebral immune changes and inflammation, contributing to neuropathology and behavioral abnormalities relevant to psychiatric disorders such as depression. Although the pathological implication of many peripheral factors such as pro‐inflammatory cytokines, hormones, and macrophages has been demonstrated, the roles of circulating extracellular vesicles (EVs) for chronic stress mechanisms remain poorly investigated. Here, we report that chronic social defeat stress (CSDS)‐induced social avoidance phenotype, assessed by a previously untested three‐chamber social approach test, can be distinguished by multiple pro‐inflammatory cytokines and EV‐associated molecular signatures in the blood. We found that the expression patterns of miRNAs distinguished the CSDS‐susceptible mice from the CSDS‐resilient mice. Social avoidance behavior scores were also estimated with good accuracy by the expression patterns of multiple EV‐associated miRNAs. We also demonstrated that EVs enriched from the CSDS‐susceptible mouse sera upregulated the production of pro‐inflammatory cytokines in the LPS‐stimulated microglia‐like cell lines. Our results indicate the role of circulating EVs and associated miRNAs in CSDS susceptibility, which may be related to pro‐inflammatory mechanisms underlying stress‐induced neurobehavioral outcomes.
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Affiliation(s)
- Shinji Sakamoto
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Dania Mallah
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA
| | - Destynie J Medeiros
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA
| | - Eisuke Dohi
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.,Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA
| | - Takashi Imai
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Indigo V L Rose
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ken Matoba
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA
| | - Xiaolei Zhu
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Atsushi Kamiya
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Shin-Ichi Kano
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.,Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA
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Jin F, Liao L, Zhu Y. MiR-467b alleviates lipopolysaccharide-induced inflammation through targeting STAT1 in chondrogenic ATDC5 cells. Int J Immunogenet 2021; 48:435-442. [PMID: 33650224 DOI: 10.1111/iji.12534] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 02/01/2021] [Accepted: 02/18/2021] [Indexed: 12/13/2022]
Abstract
Osteoarthritis (OA) is one of the most common degenerative joint diseases worldwide. Chondrocytes are activated in OA patients, accompanied by excessive chondrogenic proliferation and production of inflammatory cytokines. MiR-467b is implicated in the regulation of artherosclerosis and pro-inflammatory cytokine secretion. However, the precise role of miR-467b in OA remains unclear. In the present study, we induced inflammation in chondrogenic ATDC5 cells using lipopolysaccharide (LPS). LPS treatment significantly elevated the production of interleukin-6 (IL-6), IL-1β and tumour necrosis factor-α (TNF-α) in ATDC5 cells, accompanied by decreased miR-467 level. Then, we over-expressed miR-467b using its specific mimics in ATDC5 cells, and LPS-induced inflammation was significantly inhibited as evidenced by decreased IL-6, IL-1β and TNF-α levels. MiR-467b agomir also alleviated inflammation in rat knee osteoarthritis (KOA) model. In addition, we validated that signal transducer and activator of transcription 1 (STAT1) was a downstream target of miR-467b. LPS treatment significantly increased the STAT1 expression while miR-467b mimic transfection partially reversed this effect. Moreover, STAT1 knockout reversed the increased contents of IL-6, IL-1β and TNF-α. Furthermore, miR-467b over-expression significantly decreased the production of IL-6, IL-1β and TNF-α induced by LPS treatment, which was partially reversed by further STAT1 over-expression. In summary, our findings demonstrated that miR-467b alleviated LPS-induced inflammation through targeting STAT1, and this miR-467b/STAT1 regulation axis may provide a new therapeutic target for OA clinical management.
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Affiliation(s)
- Feng Jin
- Department of Orthopedics, Community Health Service Center of Shouxiang, Hangzhou, Zhejiang Province, China
| | - Leming Liao
- Department of Orthopedics, First People's Hospital of Fuyang District, Hangzhou, Zhejiang Province, China
| | - Yongjun Zhu
- Department of Orthopedics, Community Health Service Center of Shouxiang, Hangzhou, Zhejiang Province, China
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Gajeton J, Krukovets I, Yendamuri R, Verbovetskiy D, Vasanji A, Sul L, Stenina‐Adognravi O. miR-467 regulates inflammation and blood insulin and glucose. J Cell Mol Med 2021; 25:2549-2562. [PMID: 33566451 PMCID: PMC7933977 DOI: 10.1111/jcmm.16224] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 09/24/2020] [Accepted: 10/18/2020] [Indexed: 12/12/2022] Open
Abstract
Obesity is associated with inflammation and insulin resistance (IR), but the regulation of insulin sensitivity (IS) and connections between IS and inflammation remain unclear. We investigated the role of miR-467a-5p, a miRNA induced by hyperglycaemia, in regulating inflammation and blood glucose handling. We previously demonstrated that miR-467a-5p is induced by hyperglycaemia and inhibits the production of thrombospondin-1 (TSP-1), a protein implicated in regulating inflammation. To investigate the role of miR-467 in blood glucose handling and tissue inflammation, WT C57BL/6 mice were fed chow or Western diet from 5 to 32 weeks of age and injected weekly with miR-467a-5p antagonist. Inhibiting miR-467a-5p resulted in 47% increase in macrophage infiltration and increased Il6 levels in adipose tissue, higher plasma insulin levels (98 ng/mL vs 63 ng/mL), and 17% decrease in glucose clearance without increase in weight or HDL/LDL. The antagonist effect was lost in mice on Western diet. Mice lacking TSP-1 lost some but not all of the miR-467 effects, suggesting Thbs1 (and other unknown transcripts) are targeted by miR-467 to regulate inflammation. miR-467a-5p provides a physiological feedback when blood glucose is elevated to avoid inflammation and increased blood glucose and insulin levels, which may prevent IR.
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Affiliation(s)
- Jasmine Gajeton
- Department of Cardiovascular and Metabolic SciencesCleveland ClinicClevelandOHUSA
- Department of Molecular MedicineCase Western Reserve UniversityClevelandOHUSA
| | - Irene Krukovets
- Department of Cardiovascular and Metabolic SciencesCleveland ClinicClevelandOHUSA
| | - Revanth Yendamuri
- Department of Cardiovascular and Metabolic SciencesCleveland ClinicClevelandOHUSA
- Present address:
Northeast Ohio Medical UniversityRootstownOHUSA
| | - Dmitriy Verbovetskiy
- Department of Cardiovascular and Metabolic SciencesCleveland ClinicClevelandOHUSA
| | | | - Lidiya Sul
- Department of Cardiovascular and Metabolic SciencesCleveland ClinicClevelandOHUSA
- Present address:
Ohio University Heritage College of Osteopathic MedicineAthensOHUSA
| | - Olga Stenina‐Adognravi
- Department of Cardiovascular and Metabolic SciencesCleveland ClinicClevelandOHUSA
- Department of Molecular MedicineCase Western Reserve UniversityClevelandOHUSA
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Wu Y, Yang J, Liu X, Zhang Y, Lei A, Yi R, Tan F, Zhao X. Preventive effect of small-leaved Kuding tea ( Ligustrum robustum) on high-diet-induced obesity in C57BL/6J mice. Food Sci Nutr 2020; 8:4512-4522. [PMID: 32884731 PMCID: PMC7455952 DOI: 10.1002/fsn3.1758] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Revised: 06/09/2020] [Accepted: 06/12/2020] [Indexed: 12/11/2022] Open
Abstract
Small-leaved Kuding tea (SLKDT; Ligustrum robustum) is a traditional Chinese tea. We systematically investigated the effect of SLKDT extract on obesity. SLKDT-controlled weight gain in mice fed a high-fat diet. Tissue specimen results showed that the SLKDT extract alleviated liver damage and fat accumulation. Meanwhile, SLKDT extract improved dyslipidemia by decreasing total cholesterol, triglycerides, and low-density lipoprotein cholesterol levels and increasing high-density lipoprotein cholesterol levels. Furthermore, SLKDT extract reduced alanine aminotransferase, alkaline phosphatase, and aspartate transaminase levels in the serum and liver tissues; decreased inflammatory cytokines, including interleukin (IL)-1β, tumor necrosis factor-α, interferon-γ, and IL-6; and increased the anti-inflammatory cytokines, IL-4 and IL-10. The quantitative PCR results showed that SLKDT extract upregulated the mRNA expressions of peroxisome proliferator-activated receptor (PPAR)-α, lipoprotein lipase, carnitine palmitoyltransferase 1, and cholesterol 7 alpha hydroxylase and downregulated PPAR-γ and CCAAT/enhancer-binding protein-alpha mRNA expressions in the obese mouse livers to reduce adipocyte differentiation and fat accumulation, promote fat oxidation, and improve dyslipidemia, thereby inhibiting the immune response and alleviating liver injury. SLKDT shows a potential for preventing obesity and regulating obesity-related syndrome, so it is possible to be further developed as a novel treatment for fighting obesity.
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Affiliation(s)
- Ya Wu
- Chongqing Collaborative Innovation Center for Functional FoodChongqing University of EducationChongqingChina
- Chongqing Engineering Research Center of Functional FoodChongqing University of EducationChongqingChina
- Chongqing Engineering Laboratory for Research and Development of Functional FoodChongqing University of EducationChongqingChina
- College of Biological and Chemical EngineeringChongqing University of EducationChongqingChina
| | - Jun Yang
- Department of GastroenterologyPeople's Hospital of Chongqing Banan DistrictChongqingChina
| | - Xiaojing Liu
- Chongqing Collaborative Innovation Center for Functional FoodChongqing University of EducationChongqingChina
- College of Biological and Chemical EngineeringChongqing University of EducationChongqingChina
| | - Ying Zhang
- Chongqing Collaborative Innovation Center for Functional FoodChongqing University of EducationChongqingChina
- College of Biological and Chemical EngineeringChongqing University of EducationChongqingChina
| | - Ailing Lei
- Chongqing Collaborative Innovation Center for Functional FoodChongqing University of EducationChongqingChina
- College of Biological and Chemical EngineeringChongqing University of EducationChongqingChina
| | - Ruokun Yi
- Chongqing Collaborative Innovation Center for Functional FoodChongqing University of EducationChongqingChina
- Chongqing Engineering Research Center of Functional FoodChongqing University of EducationChongqingChina
- Chongqing Engineering Laboratory for Research and Development of Functional FoodChongqing University of EducationChongqingChina
| | - Fang Tan
- Department of Public HealthOur Lady of Fatima UniversityValenzuelaPhilippines
| | - Xin Zhao
- Chongqing Collaborative Innovation Center for Functional FoodChongqing University of EducationChongqingChina
- Chongqing Engineering Research Center of Functional FoodChongqing University of EducationChongqingChina
- Chongqing Engineering Laboratory for Research and Development of Functional FoodChongqing University of EducationChongqingChina
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Henning RJ. Cardiovascular Exosomes and MicroRNAs in Cardiovascular Physiology and Pathophysiology. J Cardiovasc Transl Res 2020; 14:195-212. [PMID: 32588374 DOI: 10.1007/s12265-020-10040-5] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Accepted: 05/26/2020] [Indexed: 12/16/2022]
Abstract
Cardiac exosomes mediate cell-to-cell communication, stimulate or inhibit the activities of target cells, and affect myocardial hypertrophy, injury and infarction, ventricular remodeling, angiogenesis, and atherosclerosis. The exosomes that are released in the heart from cardiomyocytes, vascular cells, fibroblasts, and resident stem cells are hypoimmunogenic, are physiologically more stable than cardiac cells, can circulate in the body, and are able to cross the blood-brain barrier. Exosomes utilize three mechanisms for cellular communication: (1) internalization by cells, (2) direct fusion to the cell membrane, and (3) receptor-ligand interactions. Cardiac exosomes transmit proteins, mRNA, and microRNAs to other cells during both physiological and pathological process. Cardiac-specific exosome miRNAs can regulate the expression of sarcomeric genes, ion channel genes, autophagy, anti-apoptotic and anti-fibrotic activity, and angiogenesis. This review discusses the role of exosomes and microRNAs in normal myocardium, myocardial injury and infarction, atherosclerosis, and the importance of circulating microRNAs as biomarkers of cardiac disease. Graphical Abstract.
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Affiliation(s)
- Robert J Henning
- University of South Florida, 13201 Bruce B. Downs Blvd., Tampa, FL, 33612-3805, USA.
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10
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Shoeibi S. Diagnostic and theranostic microRNAs in the pathogenesis of atherosclerosis. Acta Physiol (Oxf) 2020; 228:e13353. [PMID: 31344321 DOI: 10.1111/apha.13353] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Revised: 07/22/2019] [Accepted: 07/23/2019] [Indexed: 12/12/2022]
Abstract
MicroRNAs (miRNAs) are a group of small single strand and noncoding RNAs that regulate several physiological and molecular signalling pathways. Alterations of miRNA expression profiles may be involved with pathophysiological processes underlying the development of atherosclerosis and cardiovascular diseases, including changes in the functions of the endothelial cells and vascular smooth muscle cells, such as cell proliferation, migration and inflammation, which are involved in angiogenesis, macrophage function and foam cell formation. Thus, miRNAs can be considered to have a crucial role in the progression, modulation and regulation of every stage of atherosclerosis. Such potential biomarkers will enable us to predict therapeutic response and prognosis of cardiovascular diseases and adopt effective preclinical and clinical treatment strategies. In the present review article, the current data regarding the role of miRNAs in atherosclerosis were summarized and the potential miRNAs as prognostic, diagnostic and theranostic biomarkers in preclinical and clinical studies were further discussed. The highlights of this review are expected to present opportunities for future research of clinical therapeutic approaches in vascular diseases resulting from atherosclerosis with an emphasis on miRNAs.
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Affiliation(s)
- Sara Shoeibi
- Atherosclerosis Research Center Ahvaz Jundishapur University of Medical Sciences Ahvaz Iran
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Ma M, Wang C, Ao Y, He N, Hao F, Liang H, Liu D. HOXC10 promotes proliferation and attenuates lipid accumulation of sheep bone marrow mesenchymal stem cells. Mol Cell Probes 2019; 49:101491. [PMID: 31812713 DOI: 10.1016/j.mcp.2019.101491] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 12/03/2019] [Accepted: 12/04/2019] [Indexed: 01/19/2023]
Abstract
Homeodomain-containing gene C10 (HOXC10), known to regulate cell differentiation and proliferation, is a key negative regulator in the browning of white adipose tissue in mice. Sheep is an important farm animal that provides meat for human consumption, with fat content being an important meat quality determinant; however, there is no report about the role of HOXC10 in sheep adipocytes or adipogenesis. In this study, we investigated the effect of HOXC10 on proliferation and adipogenic differentiation in sheep bone marrow mesenchymal stem cells (sBMSCs). In sBMSCs, HOXC10 overexpression promoted cell proliferation and upregulated the expression of p-PI3K, p-AKT, p-p70S6K, p-MEK, and p-ERK, whereas HOXC10 knockdown was associated with the opposite effects. These results suggested that HOXC10 may promote cell proliferation by activating the MEK/ERK and PI3K/AKT/mTOR/p70S6K signaling pathways. In addition, we found that HOXC10 expression was negatively associated with lipid accumulation in adipogenic-differentiated sBMSCs. HOXC10 overexpression in sBMSCs significantly decreased lipid droplet accumulation and suppressed the expression of adipogenic-specific genes, including ACC, LPL, PPARG, and FABP4, while HOXC10 knockdown was associated with the opposite effects. Furthermore, our study suggested a new regulatory mechanism of the effect of HOXC10 on lipid accumulation and metabolism; HOXC10 may negatively regulate lipid accumulation in adipogenic-differentiated sBMSCs, at least in part, by suppressing LPL expression. Overall, our research not only contributes to a better understanding of the mechanism of lipid accumulation and metabolism in sheep, but also shed light on meat quality control in the future.
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Affiliation(s)
- Min Ma
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, Inner Mongolia University, Hohhot, Inner Mongolia, China
| | - Cuiru Wang
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, Inner Mongolia University, Hohhot, Inner Mongolia, China
| | - Yue Ao
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, Inner Mongolia University, Hohhot, Inner Mongolia, China
| | - Nimantana He
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, Inner Mongolia University, Hohhot, Inner Mongolia, China
| | - Fei Hao
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, Inner Mongolia University, Hohhot, Inner Mongolia, China
| | - Hao Liang
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, Inner Mongolia University, Hohhot, Inner Mongolia, China
| | - Dongjun Liu
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, Inner Mongolia University, Hohhot, Inner Mongolia, China.
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The lncRNA DAPK-IT1 regulates cholesterol metabolism and inflammatory response in macrophages and promotes atherogenesis. Biochem Biophys Res Commun 2019; 516:1234-1241. [DOI: 10.1016/j.bbrc.2019.06.113] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Accepted: 06/20/2019] [Indexed: 01/07/2023]
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Chen LY, Xia XD, Zhao ZW, Gong D, Ma XF, Yu XH, Zhang Q, Wang SQ, Dai XY, Zheng XL, Zhang DW, Yin WD, Tang CK. MicroRNA-377 Inhibits Atherosclerosis by Regulating Triglyceride Metabolism Through the DNA Methyltransferase 1 in Apolipoprotein E-Knockout Mice. Circ J 2018; 82:2861-2871. [PMID: 30232292 DOI: 10.1253/circj.cj-18-0410] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND Lipoprotein lipase (LPL) plays an important role in triglyceride metabolism. It is translocated across endothelial cells to reach the luminal surface of capillaries by glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1), where it hydrolyzes triglycerides in lipoproteins. MicroRNA 377 (miR-377) is highly associated with lipid levels. However, how miR-377 regulates triglyceride metabolism and whether it is involved in the development of atherosclerosis remain largely unexplored. METHODS AND RESULTS The clinical examination displayed that miR-377 expression was markedly lower in plasma from patients with hypertriglyceridemia compared with non-hypertriglyceridemic subjects. Bioinformatics analyses and a luciferase reporter assay showed that DNA methyltransferase 1 (DNMT1) was a target gene of miR-377. Moreover, miR-377 increased LPL binding to GPIHBP1 by directly targeting DNMT1 in human umbilical vein endothelial cells (HUVECs) and apolipoprotein E (ApoE)-knockout (KO) mice aorta endothelial cells (MAECs). In vivo, hematoxylin-eosin (H&E), Oil Red O and Masson's trichrome staining showed that ApoE-KO mice treated with miR-377 developed less atherosclerotic plaques, accompanied by reduced plasma triglyceride levels. CONCLUSIONS It is concluded that miR-377 upregulates GPIHBP1 expression, increases the LPL binding to GPIHBP1, and reduces plasma triglyceride levels, likely through targeting DNMT1, inhibiting atherosclerosis in ApoE-KO mice.
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Affiliation(s)
- Ling-Yan Chen
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China
| | - Xiao-Dan Xia
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China
| | - Zhen-Wang Zhao
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China
| | - Duo Gong
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China
| | - Xiao-Feng Ma
- Department of Internal Medicine-Cardiovascular, Nanhua Hospital, University of South China
| | - Xiao-Hua Yu
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China
| | - Qiang Zhang
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China
| | - Si-Qi Wang
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China
| | - Xiao-Yan Dai
- Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou, Medical University
| | - Xi-Long Zheng
- Department of Biochemistry and Molecular Biology, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Health Sciences Center
| | - Da-Wei Zhang
- Department of Pediatrics and Group on the Molecular and Cell Biology of Lipids, University of Alberta
| | - Wei-Dong Yin
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China
| | - Chao-Ke Tang
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China
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He PP, Jiang T, OuYang XP, Liang YQ, Zou JQ, Wang Y, Shen QQ, Liao L, Zheng XL. Lipoprotein lipase: Biosynthesis, regulatory factors, and its role in atherosclerosis and other diseases. Clin Chim Acta 2018; 480:126-137. [PMID: 29453968 DOI: 10.1016/j.cca.2018.02.006] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Revised: 02/06/2018] [Accepted: 02/07/2018] [Indexed: 01/20/2023]
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Ye Q, Tian GP, Cheng HP, Zhang X, Ou X, Yu XH, Tan RQ, Yang FY, Gong D, Huang C, Pan YJ, Zhang J, Chen LY, Zhao ZW, Xie W, Li L, Zhang M, Xia XD, Zheng XL, Tang CK. MicroRNA-134 Promotes the Development of Atherosclerosis Via the ANGPTL4/LPL Pathway in Apolipoprotein E Knockout Mice. J Atheroscler Thromb 2018; 25:244-253. [PMID: 28867683 PMCID: PMC5868510 DOI: 10.5551/jat.40212] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
AIMS Atherosclerosis is the most common cause of cardiovascular disease, such as myocardial infarction and stroke. Previous study revealed that microRNA (miR)-134 promotes lipid accumulation and proinflammatory cytokine secretion through angiopoietin-like 4 (ANGPTL4)/lipid lipoprotein (LPL) signaling in THP-1 macrophages. METHODS ApoE KO male mice on a C57BL/6 background were fed a high-fat/high-cholesterol Western diet, from 8 to 16 weeks of age. Mice were divided into four groups, and received a tail vein injection of miR-134 agomir, miR-134 antagomir, or one of the corresponding controls, respectively, once every 2 weeks after starting the Western diet. After 8 weeks we measured aortic atherosclerosis, LPL Activity, mRNA and protein levels of ANGPTL4 and LPL, LPL/ low-density lipoprotein receptor related protein 1 Complex Formation, proinflammatory cytokine secretion and lipid levels. RESULTS Despite this finding, the influence of miR-134 on atherosclerosis in vivo remains to be determined. Using the well-characterized mouse atherosclerosis model of apolipoprotein E knockout, we found that systemic delivery of miR-134 agomir markedly enhanced the atherosclerotic lesion size, together with a significant increase in proinflammatory cytokine secretion and peritoneal macrophages lipid contents. Moreover, overexpression of miR-134 decreased ANGPTL4 expression but increased LPL expression and activity in both aortic tissues and peritoneal macrophages, which was accompanied by increased formation of LPL/low-density lipoprotein receptor-related protein 1 complexes in peritoneal macrophages. However, an opposite effect was observed in response to miR-134 antagomir. CONCLUSIONS These findings suggest that miR-134 accelerates atherogenesis by promoting lipid accumulation and proinflammatory cytokine secretion via the ANGPTL4/LPL pathway. Therefore, targeting miR-134 may offer a promising strategy for the prevention and treatment of atherosclerotic cardiovascular disease.
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Affiliation(s)
- Qiong Ye
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hunan, China
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of University of South China, Hunan, China
- Department of Ultrasound, Huadu District People's Hospital of Guangzhou, Guangdong, China
| | - Guo-Ping Tian
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of University of South China, Hunan, China
| | - Hai-Peng Cheng
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hunan, China
| | - Xin Zhang
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hunan, China
| | - Xiang Ou
- Department of Endocrinology, The First Hospital of Changsha, Changsha, China
| | - Xiao-Hua Yu
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hunan, China
| | - Ru-Qi Tan
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of University of South China, Hunan, China
| | - Feng-Yun Yang
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of University of South China, Hunan, China
| | - Duo Gong
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hunan, China
| | - Chong Huang
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hunan, China
| | - Yan-Jun Pan
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of University of South China, Hunan, China
| | - Jie Zhang
- Department of Spinal Surgery, The Second Affiliated Hospital of University of South China, Hunan, China
| | - Ling-Yan Chen
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hunan, China
| | - Zhen-Wang Zhao
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hunan, China
| | - Wei Xie
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hunan, China
| | - Liang Li
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hunan, China
| | - Min Zhang
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hunan, China
| | - Xiao-Dan Xia
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hunan, China
| | - Xi-Long Zheng
- Department of Biochemistry and Molecular Biology, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Health Sciences Center, 3330 Hospital Dr NW, Calgary, Alberta, Canada
| | - Chao-Ke Tang
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hunan, China
- Address for correspondence: Chao-Ke Tang, Institute of Cardiovascular Research, University of South China, Hengyang, Hunan 421001, China E-mail:
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16
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Cheng HP, Gong D, Zhao ZW, He PP, Yu XH, Ye Q, Huang C, Zhang X, Chen LY, Xie W, Zhang M, Li L, Xia XD, Ouyang XP, Tan YL, Wang ZB, Tian GP, Zheng XL, Yin WD, Tang CK. MicroRNA-182 Promotes Lipoprotein Lipase Expression and Atherogenesisby Targeting Histone Deacetylase 9 in Apolipoprotein E-Knockout Mice. Circ J 2017; 82:28-38. [PMID: 28855441 DOI: 10.1253/circj.cj-16-1165] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND Lipoprotein lipase (LPL) expressed in macrophages plays an important role in promoting the development of atherosclerosis or atherogenesis. MicroRNA-182 (miR-182) is involved in the regulation of lipid metabolism and inflammation. However, it remains unclear how miR-182 regulates LPL and atherogenesis. METHODS AND RESULTS Using bioinformatics analyses and a dual-luciferase reporter assay, we identified histone deacetylase 9 (HDAC9) as a target gene of miR-182. Moreover, miR-182 upregulated LPL expression by directly targetingHDAC9in THP-1 macrophages. Hematoxylin-eosin (H&E), Oil Red O and Masson's trichrome staining showed that apolipoprotein E (ApoE)-knockout (KO) mice treated with miR-182 exhibited more severe atherosclerotic plaques. Treatment with miR-182 increased CD68 and LPL expression in atherosclerotic lesions in ApoE-KO mice, as indicated by double immunofluorescence staining in the aortic sinus. Increased miR-182-induced increases in LPL expression in ApoE-KO mice was confirmed by real-time quantitative polymerase chain reaction and western blotting analyses. Treatment with miR-182 also increased plasma concentrations of proinflammatory cytokines and lipids in ApoE-KO mice. CONCLUSIONS The results of the present study suggest that miR-182 upregulates LPL expression, promotes lipid accumulation in atherosclerotic lesions, and increases proinflammatory cytokine secretion, likely through targetingHDAC9, leading to an acceleration of atherogenesis in ApoE-KO mice.
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Affiliation(s)
- Hai-Peng Cheng
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China
| | - Duo Gong
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China
| | - Zhen-Wang Zhao
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China
| | - Ping-Ping He
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China
| | - Xiao-Hua Yu
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China
| | - Qiong Ye
- Department of Cardiovascular Medicine, Second Affiliated Hospital of University of South China
| | - Chong Huang
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China
| | - Xin Zhang
- School of Pharmacy and Life Science College, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China
| | - Ling-Yan Chen
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China
| | - Wei Xie
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China
| | - Min Zhang
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China
| | - Liang Li
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China
| | - Xiao-Dan Xia
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China
| | - Xin-Ping Ouyang
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China
| | - Yu-Lin Tan
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China
| | - Zong-Bao Wang
- School of Pharmacy and Life Science College, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China
| | - Guo-Ping Tian
- Department of Cardiovascular Medicine, Second Affiliated Hospital of University of South China
| | - Xi-Long Zheng
- Department of Biochemistry and Molecular Biology, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Health Sciences Center, 3330 Hospital Dr. NW
| | - Wei-Dong Yin
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China
| | - Chao-Ke Tang
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China
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17
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Zhang X, Ye Q, Gong D, Lv Y, Cheng H, Huang C, Chen L, Zhao Z, Li L, Wei X, Zhang M, Xia X, Yu X, Zheng X, Wang S, Wang Z, Tang C. Apelin-13 inhibits lipoprotein lipase expression via the APJ/PKCα/miR-361-5p signaling pathway in THP-1 macrophage-derived foam cells. Acta Biochim Biophys Sin (Shanghai) 2017; 49:530-540. [PMID: 28444107 DOI: 10.1093/abbs/gmx038] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Indexed: 12/13/2022] Open
Abstract
Atherosclerotic lesions are characterized by the accumulation of abundant lipids and chronic inflammation. Previous researches have indicated that macrophage-derived lipoprotein lipase (LPL) promotes atherosclerosis progression by accelerating lipid accumulation and pro-inflammatory cytokine secretion. Although apelin-13 has been regarded as an atheroprotective factor, it remains unclear whether it can regulate the expression of LPL. The aim of this study was to explore the effects of apelin-13 on the expression of LPL and the underlying mechanism in THP-1 macrophage-derived foam cells. Apelin-13 significantly decreased cellular levels of total cholesterol, free cholesterol, and cholesterol ester at the concentrations of 10 and 100 nM. ELISA analysis confirmed that treatment with apelin-13 reduced pro-inflammatory cytokine secretion, such as interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α). It was also found that apelin-13 inhibited the expression of LPL as revealed by western blot and real-time PCR analyses. Bioinformatics analyses and dual-luciferase reporter assay indicated that miR-361-5p directly downregulated the expression of LPL by targeting the 3'UTR of LPL. In addition, apelin-13 + miR-361-5p mimic significantly downregulated the expression of LPL in cells. Finally, we demonstrated that apelin-13 downregulated the expression of LPL through activating the activity of PKCα. Taken together, our results showed that apelin-13 downregulated the expression of LPL via activating the APJ/PKCα/miR-361-5p signaling pathway in THP-1 macrophage-derived foam cells, leading to inhibition of lipid accumulation and pro-inflammatory cytokine secretion. Therefore, our studies provide important new insight into the inhibition of lipid accumulation and pro-inflammatory cytokine secretion by apelin-13, and highlight apelin-13 as a promising therapeutic target in atherosclerosis.
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Affiliation(s)
- Xin Zhang
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang 421001, China
- Department of Biochemistry and Molecular Biology, School of Pharmacy and Life Science University of South China, Hengyang 421001, China
| | - Qiong Ye
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang 421001, China
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of University of South China, Hengyang 421001, China
| | - Duo Gong
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang 421001, China
| | - Yuan Lv
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang 421001, China
- Department of Biochemistry and Molecular Biology, School of Pharmacy and Life Science University of South China, Hengyang 421001, China
| | - Haipeng Cheng
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang 421001, China
| | - Chong Huang
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang 421001, China
| | - Lingyan Chen
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang 421001, China
| | - Zhenwang Zhao
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang 421001, China
| | - Liang Li
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang 421001, China
| | - Xie Wei
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang 421001, China
| | - Min Zhang
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang 421001, China
| | - Xiaodan Xia
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang 421001, China
| | - Xiaohua Yu
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang 421001, China
| | - Xilong Zheng
- Department of Biochemistry and Molecular Biology, Cumming School of Medicine, Libin Cardiovascular Institute of Alberta, University of Calgary, Health Sciences Center, Calgary, Alberta, CanadaT2N 4N1
| | - Shuzhi Wang
- Department of Biochemistry and Molecular Biology, School of Pharmacy and Life Science University of South China, Hengyang 421001, China
| | - Zongbao Wang
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang 421001, China
- Department of Biochemistry and Molecular Biology, School of Pharmacy and Life Science University of South China, Hengyang 421001, China
| | - Chaoke Tang
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang 421001, China
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18
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Wang B, He PP, Zeng GF, Zhang T, Ou Yang XP. miR-467b regulates the cholesterol ester formation via targeting ACAT1 gene in RAW 264.7 macrophages. Biochimie 2017; 132:38-44. [DOI: 10.1016/j.biochi.2016.09.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Revised: 09/22/2016] [Accepted: 09/22/2016] [Indexed: 12/01/2022]
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Xie W, Li L, Zhang M, Cheng HP, Gong D, Lv YC, Yao F, He PP, Ouyang XP, Lan G, Liu D, Zhao ZW, Tan YL, Zheng XL, Yin WD, Tang CK. MicroRNA-27 Prevents Atherosclerosis by Suppressing Lipoprotein Lipase-Induced Lipid Accumulation and Inflammatory Response in Apolipoprotein E Knockout Mice. PLoS One 2016; 11:e0157085. [PMID: 27257686 PMCID: PMC4892477 DOI: 10.1371/journal.pone.0157085] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Accepted: 05/24/2016] [Indexed: 01/11/2023] Open
Abstract
Atherosclerotic lesions are lipometabolic disorder characterized by chronic progressive inflammation in arterial walls. Previous studies have shown that macrophage-derived lipoprotein lipase (LPL) might be a key factor that promotes atherosclerosis by accelerating lipid accumulation and proinflammatory cytokine secretion. Increasing evidence indicates that microRNA-27 (miR-27) has beneficial effects on lipid metabolism and inflammatory response. However, it has not been fully understood whether miR-27 affects the expression of LPL and subsequent development of atherosclerosis in apolipoprotein E knockout (apoE KO) mice. To address these questions and its potential mechanisms, oxidized low-density lipoprotein (ox-LDL)-treated THP-1 macrophages were transfected with the miR-27 mimics/inhibitors and apoE KO mice fed high-fat diet were given a tail vein injection with miR-27 agomir/antagomir, followed by exploring the potential roles of miR-27. MiR-27 agomir significantly down-regulated LPL expression in aorta and peritoneal macrophages by western blot and real-time PCR analyses. We performed LPL activity assay in the culture media and found that miR-27 reduced LPL activity. ELISA showed that miR-27 reduced inflammatory response as analyzed in vitro and in vivo experiments. Our results showed that miR-27 had an inhibitory effect on the levels of lipid both in plasma and in peritoneal macrophages of apoE KO mice as examined by HPLC. Consistently, miR-27 suppressed the expression of scavenger receptors associated with lipid uptake in ox-LDL-treated THP-1 macrophages. In addition, transfection with LPL siRNA inhibited the miR-27 inhibitor-induced lipid accumulation and proinflammatory cytokines secretion in ox-LDL-treated THP-1 macrophages. Finally, systemic treatment revealed that miR-27 decreased aortic plaque size and lipid content in apoE KO mice. The present results provide evidence that a novel antiatherogenic role of miR-27 was closely related to reducing lipid accumulation and inflammatory response via downregulation of LPL gene expression, suggesting a potential strategy to the diagnosis and treatment of atherosclerosis.
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Affiliation(s)
- Wei Xie
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan, China.,Laboratory of Clinical Anatomy, University of South China, Hengyang, Hunan, China
| | - Liang Li
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan, China.,Department of Pathophysiology, University of South China, Hengyang, Hunan, China
| | - Min Zhang
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan, China
| | - Hai-Peng Cheng
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan, China
| | - Duo Gong
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan, China
| | - Yun-Cheng Lv
- Laboratory of Clinical Anatomy, University of South China, Hengyang, Hunan, China
| | - Feng Yao
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan, China
| | - Ping-Ping He
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan, China
| | - Xin-Ping Ouyang
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan, China
| | - Gang Lan
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan, China
| | - Dan Liu
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan, China
| | - Zhen-Wang Zhao
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan, China
| | - Yu-Lin Tan
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan, China
| | - Xi-Long Zheng
- Department of Biochemistry and Molecular Biology, The Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, The University of Calgary, Health Sciences Center, Hospital Dr NW, Calgary, Alberta, Canada
| | - Wei-Dong Yin
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan, China
| | - Chao-Ke Tang
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan, China
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Peng J, Lv YC, He PP, Tang YY, Xie W, Liu XY, Li Y, Lan G, Zhang M, Zhang C, Shi JF, Zheng XL, Yin WD, Tang CK. RETRACTED:Betulinic acid downregulates expression of oxidative stress-induced lipoprotein lipase via the PKC/ERK/c-Fos pathway in RAW264.7 macrophages. Biochimie 2015; 119:192-203. [PMID: 26542288 DOI: 10.1016/j.biochi.2015.10.020] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2015] [Accepted: 10/28/2015] [Indexed: 12/22/2022]
Abstract
This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief. Concerns raised by Dr. Sander Kersten in PubPeer pointed out that Figures 6.1B and 6.2B of this paper were different figures but the legends and Western blots were identical; the quantification was also seen to be different between the two figures. Shortly afterwards, the authors asked to publish a corrigendum for part B of Figure 6.1, including images of western blots and associated bar plots. Subsequently, the journal conducted an investigation and found evidence that there had been improper manipulation and duplication of images in Figures 2 E, 6.2 B, 5 A and and 6.2 D, as shown by the reuse of several western blot bands with approximately 180° rotation in each case. After raising the complaint with the authors, the corresponding author agreed that the paper should be retracted. The authors apologise to the readers of the journal.
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Affiliation(s)
- Juan Peng
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Hunan Province Cooperative innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, China; Yongzhou Vocational and Technical College, Yongzhou, Hunan 425000, China
| | - Yun-Cheng Lv
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Hunan Province Cooperative innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, China
| | - Ping-Ping He
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Hunan Province Cooperative innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, China; School of Nursing, University of South China, Hengyang, Hunan 421001, China
| | - Yan-Yan Tang
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Hunan Province Cooperative innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, China
| | - Wei Xie
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Hunan Province Cooperative innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, China
| | - Xiang-Yu Liu
- Department of Biochemistry and Molecular Biology, School of Life Sciences and Technology, University of South, Hengyang, Hunan 421001, China
| | - Yuan Li
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Hunan Province Cooperative innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, China
| | - Gan Lan
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Hunan Province Cooperative innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, China
| | - Min Zhang
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Hunan Province Cooperative innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, China
| | - Chi Zhang
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Hunan Province Cooperative innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, China
| | - Jin-Feng Shi
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Hunan Province Cooperative innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, China
| | - Xi-Long Zheng
- Department of Biochemistry and Molecular Biology, The Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, The University of Calgary, 3330 Hospital Dr NW, Calgary, Alberta T2N 4N1, Canada
| | - Wei-Dong Yin
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Hunan Province Cooperative innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, China.
| | - Chao-Ke Tang
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Hunan Province Cooperative innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, China.
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Lan G, Xie W, Li L, Zhang M, Liu D, Tan YL, Cheng HP, Gong D, Huang C, Zheng XL, Yin WD, Tang CK. MicroRNA-134 actives lipoprotein lipase-mediated lipid accumulation and inflammatory response by targeting angiopoietin-like 4 in THP-1 macrophages. Biochem Biophys Res Commun 2015; 472:410-7. [PMID: 26546816 DOI: 10.1016/j.bbrc.2015.10.158] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2015] [Accepted: 10/30/2015] [Indexed: 12/22/2022]
Abstract
Angiopoietin-like 4 (Angptl4), a secreted protein, is an important regulator to irreversibly inhibit lipoprotein lipase (LPL) activity. Macrophage LPL contributes to foam cell formation via a so-called"molecular bridge" between lipoproteins and receptors on cell surface. It has been reported that macrophage ANGPTL4 suppresses LPL activity, foam cell formation and inflammatory gene expression to reduce atherosclerosis development. Recently, some studies demonstrated that microRNA-134 is upregulated in atherosclerotic macrophages. Here we demonstrate that miR-134 directly binds to 3'UTR of ANGPTL4 mRNA to suppression the expression of ANGPTL4. To investigate the potential roles of macrophage miR-134, THP-1 macrophages were transfected with miR-134 mimics or inhibitors. Our results showed that LPL activity and protein were dramatically increased. We also found that miR-134 activated LPL-mediated lipid accumulation. Collectively, our findings indicate that miR-134 may regulate lipid accumulation and proinfiammatory cytokine secretion in macrophages by targeting the ANGPTL4 gene. Our results have also suggested a promising and potential therapeutic target for atherosclerosis.
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Affiliation(s)
- Gang Lan
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Life Science Research Center, University of South China, Hengyang, 421001, Hunan, China
| | - Wei Xie
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Life Science Research Center, University of South China, Hengyang, 421001, Hunan, China
| | - Liang Li
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Life Science Research Center, University of South China, Hengyang, 421001, Hunan, China
| | - Min Zhang
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Life Science Research Center, University of South China, Hengyang, 421001, Hunan, China
| | - Dan Liu
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Life Science Research Center, University of South China, Hengyang, 421001, Hunan, China
| | - Yu-Lin Tan
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Life Science Research Center, University of South China, Hengyang, 421001, Hunan, China
| | - Hai-Peng Cheng
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Life Science Research Center, University of South China, Hengyang, 421001, Hunan, China
| | - Duo Gong
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Life Science Research Center, University of South China, Hengyang, 421001, Hunan, China
| | - Chong Huang
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Life Science Research Center, University of South China, Hengyang, 421001, Hunan, China
| | - Xi-Long Zheng
- Department of Biochemistry and Molecular Biology, The Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, The University of Calgary, Health Sciences Center, 3330 Hospital Dr NW, Calgary, Alberta, T2N 4N1, Canada
| | - Wei-Dong Yin
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Life Science Research Center, University of South China, Hengyang, 421001, Hunan, China.
| | - Chao-Ke Tang
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Life Science Research Center, University of South China, Hengyang, 421001, Hunan, China.
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miR-223 Inhibits Lipid Deposition and Inflammation by Suppressing Toll-Like Receptor 4 Signaling in Macrophages. Int J Mol Sci 2015; 16:24965-82. [PMID: 26492242 PMCID: PMC4632784 DOI: 10.3390/ijms161024965] [Citation(s) in RCA: 82] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2015] [Revised: 09/04/2015] [Accepted: 09/20/2015] [Indexed: 12/16/2022] Open
Abstract
Atherosclerosis and its complications rank as the leading cause of death with the hallmarks of lipid deposition and inflammatory response. MicroRNAs (miRNAs) have recently garnered increasing interests in cardiovascular disease. In this study, we investigated the function of miR-223 and the underlying mechanism in atherosclerosis. In the atherosclerotic ApoE−/− mice models, an obvious increase of miR-223 was observed in aortic atherosclerotic lesions. In lipopolysaccharide (LPS) activated macrophages, its expression was decreased. The miR-223 overexpression significantly attenuated macrophage foam cell formation, lipid accumulation and pro-inflammatory cytokine production, which were reversed by anti-miR-223 inhibitor transfection. Mechanism assay corroborated that miR-223 negatively regulated the activation of the toll-like receptor 4 (TLR4)-nuclear factor-κB (NF-κB) pathway. Pretreatment with a specific inhibitor of NF-κB (pyrrolidinedithiocarbamate, PDTC) strikingly abrogated miR-223 silence-induced lipid deposition and inflammatory cytokine production. Furthermore, PI3K/AKT was activated by miR-223 up-regulation. Pretreatment with PI3K/AKT inhibitor LY294002 strikingly ameliorated the inhibitory effects of miR-223 on the activation of TLR4 and p65, concomitant with the increase in lipid deposition and inflammatory cytokine production. Together, these data indicate that miR-223 up-regulation might abrogate the development of atherosclerosis by blocking TLR4 signaling through activation of the PI3K/AKT pathway, and provides a promising therapeutic avenue for the treatment of atherosclerosis.
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Leti F, Malenica I, Doshi M, Courtright A, Van Keuren-Jensen K, Legendre C, Still CD, Gerhard GS, DiStefano JK. High-throughput sequencing reveals altered expression of hepatic microRNAs in nonalcoholic fatty liver disease-related fibrosis. Transl Res 2015; 166:304-14. [PMID: 26001595 PMCID: PMC4537840 DOI: 10.1016/j.trsl.2015.04.014] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2015] [Revised: 04/08/2015] [Accepted: 04/28/2015] [Indexed: 12/11/2022]
Abstract
Recent evidence suggests that microRNAs (miRNAs), small, noncoding RNA molecules that regulate gene expression, may play a role in the regulation of metabolic disorders, including nonalcoholic fatty liver disease (NAFLD). To identify miRNAs that mediate NAFLD-related fibrosis, we used high-throughput sequencing to assess miRNAs obtained from liver biopsies of 15 individuals without NAFLD fibrosis (F0) and 15 individuals with severe NAFLD fibrosis or cirrhosis (F3-F4), matched for age, sex, body mass index, type 2 diabetes status, hemoglobin A1c, and use of diabetes medications. We used DESeq2 and Kruskal-Wallis test to identify miRNAs that were differentially expressed between NAFLD patients with or without fibrosis, adjusting for multiple testing using Bonferroni correction. We identified a total of 75 miRNAs showing statistically significant evidence (adjusted P value <0.05) for differential expression between the 2 groups, including 30 upregulated and 45 downregulated miRNAs. Quantitative reverse-transcription polymerase chain reaction analysis of selected miRNAs identified by sequencing validated 9 of 11 of the top differentially expressed miRNAs. We performed functional enrichment analysis of dysregulated miRNAs and identified several potential gene targets related to NAFLD-related fibrosis including hepatic fibrosis, hepatic stellate cell activation, transforming growth factor beta signaling, and apoptosis signaling. We identified forkhead box O3 and F-box WD repeat domain containing 7, E3 ubiquitin protein ligase (FBXW7) as potential targets of miR-182, and found that levels of forkhead box O3, but not FBXW7, were significantly decreased in fibrotic samples. These findings support a role for hepatic miRNAs in the pathogenesis of NAFLD-related fibrosis and yield possible new insight into the molecular mechanisms underlying the initiation and progression of liver fibrosis and cirrhosis.
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Affiliation(s)
- Fatjon Leti
- Division of Diabetes, Cardiovascular and Metabolic Diseases, Translational Genomics Research Institute, Phoenix, Ariz
| | - Ivana Malenica
- Division of Diabetes, Cardiovascular and Metabolic Diseases, Translational Genomics Research Institute, Phoenix, Ariz
| | - Meera Doshi
- Division of Diabetes, Cardiovascular and Metabolic Diseases, Translational Genomics Research Institute, Phoenix, Ariz
| | - Amanda Courtright
- Division of Diabetes, Cardiovascular and Metabolic Diseases, Translational Genomics Research Institute, Phoenix, Ariz
| | - Kendall Van Keuren-Jensen
- Division of Diabetes, Cardiovascular and Metabolic Diseases, Translational Genomics Research Institute, Phoenix, Ariz
| | - Christophe Legendre
- Division of Diabetes, Cardiovascular and Metabolic Diseases, Translational Genomics Research Institute, Phoenix, Ariz
| | - Christopher D Still
- Department of Gastroenterology and Nutrition, Geisinger Obesity Institute, Danville, PA
| | - Glenn S Gerhard
- Department of Biochemistry and Molecular Biology, Temple University School of Medicine, Philadelphia, PA
| | - Johanna K DiStefano
- Division of Diabetes, Cardiovascular and Metabolic Diseases, Translational Genomics Research Institute, Phoenix, Ariz.
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Hartmann P, Schober A, Weber C. Chemokines and microRNAs in atherosclerosis. Cell Mol Life Sci 2015; 72:3253-66. [PMID: 26001902 PMCID: PMC4531138 DOI: 10.1007/s00018-015-1925-z] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2015] [Revised: 04/09/2015] [Accepted: 05/05/2015] [Indexed: 01/10/2023]
Abstract
The crucial role of chemokines in the initiation and progression of atherosclerosis has been widely recognized. Through essential functions in leukocyte recruitment, chemokines govern the infiltration with mononuclear cells and macrophage accumulation in atherosclerotic lesions. Beyond recruitment, chemokines also provide homeostatic functions supporting cell survival and mediating the mobilization and homing of progenitor cells. As a new regulatory layer, several microRNAs (miRNAs) have been found to modulate the function of endothelial cells (ECs), smooth muscle cells and macrophages by controlling the expression levels of chemokines and thereby affecting different stages in the progression of atherosclerosis. For instance, the expression of CXCL1 can be down-regulated by miR-181b, which inhibits nuclear factor-κB activation in atherosclerotic endothelium, thus attenuating the adhesive properties of ECs and exerting early atheroprotective effects. Conversely, CXCL12 expression can be induced by miR-126 in ECs through an auto-amplifying feedback loop to facilitate endothelial regeneration, thus limiting atherosclerosis and mediating plaque stabilization. In contrast, miR-155 plays a pro-atherogenic role by promoting the expression of CCL2 in M1-type macrophages, thereby enhancing vascular inflammation. Herein, we will review novel aspects of chemokines and their regulation by miRNAs during atherogenesis. Understanding the complex cross-talk of miRNAs controlling chemokine expression may open novel therapeutic options to treat atherosclerosis.
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Affiliation(s)
- Petra Hartmann
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany
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Abstract
Atherosclerosis is characterised by the accumulation of lipid-laden macrophages in atherosclerotic lesions and occurs preferentially at arterial branching points, which are prone to inflammation during hyperlipidaemic stress. The increased susceptibility at branching sites of arteries is attributable to poor adaptation of arterial endothelial cells to disturbed blood flow. In the past 5 years, several studies have provided mechanistic insights into the regulatory roles of microRNAs (miRNAs) in inflammatory activation, proliferation, and regeneration of endothelial cells during this maladaptive process. The intercellular transfer of vesicle-bound miRNAs contributes to arterial homeostasis, and the combinatorial effect of multiple miRNAs controls the unresolved inflammation orchestrated by macrophages in atherosclerotic lesions. In this Review, we highlight the miRNA-dependent regulation of the endothelial phenotype and the proliferative reserve that occurs in response to altered haemodynamic conditions as a prerequisite for atherogenic inflammation. In particular, we discuss the regulation of transcriptional modules by miRNAs and the protective role of complementary strand pairs, which encompasses remote miRNA signalling. In addition, we review the roles of miRNA tandems and describe the relevance of RNA target selection and competition to the behaviour of lesional macrophages. Elucidating miRNA-mediated regulatory mechanisms can aid the development of novel diagnostic and therapeutic strategies for atherosclerosis.
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Gerhard GS, DiStefano JK. Micro RNAs in the development of non-alcoholic fatty liver disease. World J Hepatol 2015; 7:226-234. [PMID: 25729477 PMCID: PMC4342604 DOI: 10.4254/wjh.v7.i2.226] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2014] [Revised: 10/16/2014] [Accepted: 11/19/2014] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease or nonalcoholic fatty liver disease (NAFLD) refers to a group of disorders that arise from the accrual of fat in hepatocytes. Although various factors have been associated with the development of NAFLD, including genetic predisposition and environmental exposures, little is known about the underlying pathogenesis of the disease. Research efforts are ongoing to identify biological targets and signaling pathways that mediate NAFLD. Emerging evidence has implicated a role for micro RNAs (miRNAs), short single-stranded molecules that regulate gene expression either transcriptionally, through targeting of promoter regions, or post-transcriptionally, by blocking translation or promoting cleavage of specific target mRNAs. Several miRNAs have been associated with NAFLD, although our understanding of the biology underlying their role is still emerging. The goal of this review is to present an overview of the current state of knowledge of miRNAs involved in the development of NAFLD across a range of in vitro and in vivo models, including miRNAs that contribute to pathological mechanisms related to fatty liver in humans. Much less is known about the specific targets of miRNAs in cells, nor the molecular mechanisms involved in the development and progression NAFLD and related outcomes. More recently, the identification and validation of miRNA signatures in serum may facilitate the development of improved methods for diagnosis and clinical monitoring of disease progression.
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Hosin AA, Prasad A, Viiri LE, Davies AH, Shalhoub J. MicroRNAs in atherosclerosis. J Vasc Res 2014; 51:338-49. [PMID: 25500818 DOI: 10.1159/000368193] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2014] [Accepted: 08/12/2014] [Indexed: 11/19/2022] Open
Abstract
Micro-ribonucleic acids (miRNAs) are a class of endogenous non-coding ribonucleic acids that regulate gene expression. MiRNAs have been shown to act as key regulators in the vascular system, with wide-ranging physio-pathological effects. Atherosclerotic disease is a leading cause of morbidity and mortality worldwide. This review presents current knowledge on miRNAs implicated in atherosclerosis susceptibility, development and progression. They are involved in cell phenotype switching, response to shear stress, cell senescence, adhesion molecule expression, macrophage response to oxidised low-density lipoprotein, Toll-like receptor 4 expression, neointimal lesion formation, plaque angiogenesis and cellular cholesterol homeostasis. Clinically, early work has demonstrated the utility of miRNAs for differentiating patients with arterial disease from controls and predicting future cardiac events; this highlights potential diagnostic and prognostic roles. MiRNA involvement in the crucial stages of atherosclerosis promises new hope in treating arterial disease. However, issues regarding multiple miRNA targets, stability and delivery continue to present challenges.
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Li Y, He PP, Zhang DW, Zheng XL, Cayabyab FS, Yin WD, Tang CK. Lipoprotein lipase: from gene to atherosclerosis. Atherosclerosis 2014; 237:597-608. [PMID: 25463094 DOI: 10.1016/j.atherosclerosis.2014.10.016] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2014] [Revised: 10/13/2014] [Accepted: 10/13/2014] [Indexed: 01/21/2023]
Abstract
Lipoprotein lipase (LPL) is a key enzyme in lipid metabolism and responsible for catalyzing lipolysis of triglycerides in lipoproteins. LPL is produced mainly in adipose tissue, skeletal and heart muscle, as well as in macrophage and other tissues. After synthesized, it is secreted and translocated to the vascular lumen. LPL expression and activity are regulated by a variety of factors, such as transcription factors, interactive proteins and nutritional state through complicated mechanisms. LPL with different distributions may exert distinct functions and have diverse roles in human health and disease with close association with atherosclerosis. It may pose a pro-atherogenic or an anti-atherogenic effect depending on its locations. In this review, we will discuss its gene, protein, synthesis, transportation and biological functions, and then focus on its regulation and relationship with atherosclerosis and potential underlying mechanisms. The goal of this review is to provide basic information and novel insight for further studies and therapeutic targets.
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Affiliation(s)
- Yuan Li
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Discovery, Life Science Research Center, University of South China, Hengyang, Hunan 421001, China
| | - Ping-Ping He
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Discovery, Life Science Research Center, University of South China, Hengyang, Hunan 421001, China; School of Nursing, University of South China, Hengyang, Hunan 421001, China
| | - Da-Wei Zhang
- Department of Pediatrics and Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta T6G 2S2, Canada
| | - Xi-Long Zheng
- Department of Biochemistry and Molecular Biology, The Libin Cardiovascular Institute of Alberta, The Cumming School of Medicine, The University of Calgary, Health Sciences Center, 3330 Hospital Dr NW, Calgary, Alberta T2N 4N1, Canada
| | - Fracisco S Cayabyab
- Department of Surgery, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Wei-Dong Yin
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Discovery, Life Science Research Center, University of South China, Hengyang, Hunan 421001, China.
| | - Chao-Ke Tang
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Discovery, Life Science Research Center, University of South China, Hengyang, Hunan 421001, China.
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29
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He PP, Ouyang XP, Tang YY, Liao L, Wang ZB, Lv YC, Tian GP, Zhao GJ, Huang L, Yao F, Xie W, Tang YL, Chen WJ, Zhang M, Li Y, Wu JF, Peng J, Liu XY, Zheng XL, Yin WD, Tang CK. MicroRNA-590 attenuates lipid accumulation and pro-inflammatory cytokine secretion by targeting lipoprotein lipase gene in human THP-1 macrophages. Biochimie 2014; 106:81-90. [PMID: 25149060 DOI: 10.1016/j.biochi.2014.08.003] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2014] [Accepted: 08/08/2014] [Indexed: 10/24/2022]
Abstract
BACKGROUND Accumulating evidence suggests that microRNA-590 (miR-590) has protective effects on cardiovascular diseases, but the mechanism is unknown. Interestingly, previous studies from our laboratory and others have shown that macrophage-derived lipoprotein lipase (LPL) might accelerate atherosclerosis by promoting lipid accumulation and inflammatory response. However, the regulation of LPL at the post-transcriptional level by microRNAs has not been fully understood. In this study, we explored whether miR-590 affects the expression of LPL and its potential subsequent effects on lipid accumulation and pro-inflammatory cytokine secretion in human THP-1 macrophages. METHODS AND RESULTS Using bioinformatics analyses and dual-luciferase reporter assays, we found that miR-590 directly inhibited LPL protein and mRNA expression by targeting LPL 3'UTR. LPL Activity Assays showed that miR-590 reduced LPL activity in the culture media. Oil Red O staining and high-performance liquid chromatography assays showed that miR-590 had inhibitory effects on the lipid accumulation in human THP-1 macrophages. We also illustrated that miR-590 alleviated pro-inflammatory cytokine secretion in human THP-1 macrophages as measured by ELISA. With the method of small interfering RNA, we found that LPL siRNA can inhibit the miR-590 inhibitor-induced increase in lipid accumulation and secretion of pro-inflammatory cytokines in oxLDL-treated human THP-1 macrophages. CONCLUSIONS MiR-590 attenuates lipid accumulation and pro-inflammatory cytokine secretion by targeting LPL gene in human THP-1 macrophages. Therefore, targeting miR-590 may offer a promising strategy to treat atherosclerotic cardiovascular diseases.
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Affiliation(s)
- Ping-Ping He
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, China; School of Nursing, University of South China, Hengyang, Hunan 421001, China
| | - Xin-Ping Ouyang
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, China; Department of Physiology, The Neuroscience Institute, Medical College, University of South China, Hengyang, Hunan 421001, China
| | - Yan-Yan Tang
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, China
| | - Li Liao
- School of Nursing, University of South China, Hengyang, Hunan 421001, China
| | - Zong-Bao Wang
- Pharmacy and Biological Science College, University of South China, Hengyang, Hunan 421001, China
| | - Yun-Cheng Lv
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, China
| | - Guo-Ping Tian
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, China; Second Affiliated Hospital of University of South China, Hengyang, Hunan 421001, China
| | - Guo-Jun Zhao
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, China
| | - Liang Huang
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, China
| | - Feng Yao
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, China
| | - Wei Xie
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, China
| | - Yu Lin Tang
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, China
| | - Wu-Jun Chen
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, China
| | - Min Zhang
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, China
| | - Yuan Li
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, China
| | - Jian-Feng Wu
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, China
| | - Juan Peng
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, China
| | - Xiang-Yu Liu
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, China
| | - Xi-Long Zheng
- Department of Biochemistry and Molecular Biology, The Libin Cardiovascular Institute of Alberta, The University of Calgary, Health Sciences Center, 3330 Hospital Dr NW, Calgary, Alberta T2N 4N1, Canada
| | - Wei-Dong Yin
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, China; Pharmacy and Biological Science College, University of South China, Hengyang, Hunan 421001, China.
| | - Chao-Ke Tang
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, China.
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Kumar S, Kim CW, Simmons RD, Jo H. Role of flow-sensitive microRNAs in endothelial dysfunction and atherosclerosis: mechanosensitive athero-miRs. Arterioscler Thromb Vasc Biol 2014; 34:2206-16. [PMID: 25012134 DOI: 10.1161/atvbaha.114.303425] [Citation(s) in RCA: 198] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Atherosclerosis preferentially occurs in arterial regions exposed to disturbed flow, in part, due to alterations in gene expression. MicroRNAs (miRNAs) are small, noncoding genes that post-transcriptionally regulate gene expression by targeting messenger RNA transcripts. Emerging evidence indicates that alteration of flow conditions regulate expression of miRNAs in endothelial cells both in vitro and in vivo. These flow-sensitive miRNAs, known as mechano-miRs, regulate endothelial gene expression and can regulate endothelial dysfunction and atherosclerosis. MiRNAs such as, miR-10a, miR-19a, miR-23b, miR-17-92, miR-21, miR-663, miR-92a, miR-143/145, miR-101, miR-126, miR-712, miR-205, and miR-155, have been identified as mechano-miRs. Many of these miRNAs were initially identified as flow sensitive in vitro and were later found to play a critical role in endothelial function and atherosclerosis in vivo through either gain-of-function or loss-of-function approaches. The key signaling pathways that are targeted by these mechano-miRs include the endothelial cell cycle, inflammation, apoptosis, and nitric oxide signaling. Furthermore, we have recently shown that the miR-712/205 family, which is upregulated by disturbed flow, contributes to endothelial inflammation and vascular hyperpermeability by targeting tissue inhibitor of metalloproteinase-3, which regulates metalloproteinases and a disintegrin and metalloproteinases. The mechano-miRs that are implicated in atherosclerosis are termed as mechanosensitive athero-miRs and are potential therapeutic targets to prevent or treat atherosclerosis. This review summarizes the current knowledge of mechanosensitive athero-miRs and their role in vascular biology and atherosclerosis.
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Affiliation(s)
- Sandeep Kumar
- From the Wallace H. Coulter Department of Biomedical Engineering (S.K., C.W.K., R.D.S., H.J.) and Division of Cardiology (H.J.), Georgia Institute of Technology and Emory University, Atlanta, GA
| | - Chan Woo Kim
- From the Wallace H. Coulter Department of Biomedical Engineering (S.K., C.W.K., R.D.S., H.J.) and Division of Cardiology (H.J.), Georgia Institute of Technology and Emory University, Atlanta, GA
| | - Rachel D Simmons
- From the Wallace H. Coulter Department of Biomedical Engineering (S.K., C.W.K., R.D.S., H.J.) and Division of Cardiology (H.J.), Georgia Institute of Technology and Emory University, Atlanta, GA
| | - Hanjoong Jo
- From the Wallace H. Coulter Department of Biomedical Engineering (S.K., C.W.K., R.D.S., H.J.) and Division of Cardiology (H.J.), Georgia Institute of Technology and Emory University, Atlanta, GA.
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