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Tian W, Ju J, Guan B, Wang T, Zhang J, Song L, Xu H. Role of hyperhomocysteinemia in atherosclerosis: from bench to bedside. Ann Med 2025; 57:2457527. [PMID: 39898976 PMCID: PMC11792134 DOI: 10.1080/07853890.2025.2457527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Revised: 01/07/2025] [Accepted: 01/08/2025] [Indexed: 02/04/2025] Open
Abstract
BACKGROUND Atherosclerosis is a leading cause of global mortality, driven by complex interactions between genetic, metabolic, and environmental factors. Among these, hyperhomocysteinemia (HHcy) has emerged as a significant and modifiable risk factor, contributing to endothelial dysfunction, oxidative stress, and vascular inflammation. Despite increasing recognition of its role in atherogenesis, the precise mechanisms and clinical implications of HHcy remain incompletely understood, necessitating a comprehensive review to connect recent mechanistic insights with practical applications. METHODS We analyzed the various mechanisms whereby HHcy accelerates the progression of atherosclerosis, and conducted a comprehensive review of publications in the fields of HHcy and atherosclerosis. RESULTS HHcy promotes atherosclerosis through several mechanisms, including inflammation, oxidative stress, epigenetic modification, and lipoprotein metabolism alteration. Moreover, this discussion extends to current strategies for the prevention and clinical management of HHcy-induced atherosclerosis. CONCLUSION This review consolidates and elucidates the latest advancements and insights into the role of HHcy in atherosclerosis. The comprehensive narrative connects fundamental research with clinical applications. Contemporary studies highlight the complex interplay between HHcy and atherosclerosis, establishing HHcy as not only a contributing risk factor but also an accelerator of various atherogenic processes.
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Affiliation(s)
- Wende Tian
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing China
- Graduate School, China Academy of Chinese Medical Sciences, Beijing China
| | - Jianqing Ju
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing China
| | - Baoyi Guan
- Department of Internal Medicine-Cardiovascular, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Tongxin Wang
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing China
- Graduate School, China Academy of Chinese Medical Sciences, Beijing China
| | - Jiqian Zhang
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing China
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Luxia Song
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing China
| | - Hao Xu
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing China
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Yang Y, Chen Y, Tang JY, Chen J, Li GQ, Feng B, Mu J. MiR-29a-3p inhibits fibrosis of diabetic kidney disease in diabetic mice via downregulation of DNA methyl transferase 3A and 3B. World J Diabetes 2025; 16:93630. [PMID: 40236856 PMCID: PMC11947916 DOI: 10.4239/wjd.v16.i4.93630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Revised: 09/16/2024] [Accepted: 01/20/2025] [Indexed: 02/28/2025] Open
Abstract
BACKGROUND At present, the incidence of diabetic nephropathy is increasing year by year, and there are many studies on the pathogenesis of diabetic nephropathy, but it is still not completely clear. The final pathological result of diabetic nephropathy is mainly glomerular cell fibrosis, and the roles of micro-RNA (miRNA)-29 and DNA methyl transferase (DNMTs) in cell fibrosis have been confirmed in other studies, but there is a lack of relevant research in the kidney at present. AIM To study the potential involvement of miRNA-29a-3p in fibrosis related to diabetic kidney disease (DKD). METHODS The expression of miR-29a-3p, DNMT3A/3B, fibrosis-related molecules, Wnt3a, β-catenin, Janus kinase 2, and signal transducer and activator of transcription 3 was assessed in SV40MES13 cells and diabetic mice using quantitative real-time PCR and western blotting. Furthermore, the expression changes of fibrosis-related molecules were further analyzed using immunofluorescence and immunohistochemical blotting. The renal pathological changes of DKD in each group were also studied using hematoxylin-eosin and periodate-Schiff reaction staining. RESULTS In both the in vivo and in vitro experiments, it was observed that high glucose induction significantly decreased miR-29a-3p expression. As a result of this downregulation, DKD-related fibrosis was found to be promoted, as confirmed by elevated expression levels of α-smooth muscle actin, collagen type I, and fibronectin. MiR-29a-3p targets the 3' non-coding regions of DNMT3A and DNMT3B and inhibits their expression. Inhibition of DNMT3A and DNMT3B can reverse the effect of miR-29a-3p downregulation on DKD-related fibrosis. CONCLUSION MiR-29a-3p can regulate Wnt/β-catenin and Janus kinase/signal transducer and activator of transcription signal pathways by regulating and inhibiting the expression of DNMT3A/3B and thus participate in the inhibition of DKD-related fibrosis.
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Affiliation(s)
- Ying Yang
- Department of Nephrology, University-Town Hospital of Chongqing Medical University, Chongqing 401331, China
| | - Yi Chen
- Department of Nephrology, University-Town Hospital of Chongqing Medical University, Chongqing 401331, China
| | - Jian-Ying Tang
- Department of Nephrology, University-Town Hospital of Chongqing Medical University, Chongqing 401331, China
| | - Jian Chen
- Institute of Immunology, The Third Military Medical University, Chongqing 400038, China
| | - Gui-Qing Li
- Institute of Immunology, The Third Military Medical University, Chongqing 400038, China
| | - Bing Feng
- Department of Nephrology, Third Military Medical University, Chongqing 400038, China
| | - Jiao Mu
- Department of Nephrology, Chongqing Medical University, Chongqing 401331, China
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Khan K, Khan A, Rahman ZU, Khan F, Latief N, Fazal N. Genetic Polymorphism in miRNA Genes and Their Association with susceptibility of Coronary Heart Disease: An Updated Review. Pathol Res Pract 2024; 264:155675. [PMID: 39488988 DOI: 10.1016/j.prp.2024.155675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 10/18/2024] [Accepted: 10/24/2024] [Indexed: 11/05/2024]
Abstract
Coronary heart disease (CHD) remains a major public health concern worldwide, with a complex interplay of genetic, environmental and lifestyle factors contributing to its pathogenesis. The potential significance of microRNAs (miRNAs) in the onset and progression of CHD has attracted increasing attention in recent years. Small non-coding RNA molecules called miRNAs control gene expression at the post-transcriptional level. Dysregulation of miRNAs has been linked to a variety of biological processes, including cell division, proliferation, apoptosis, and inflammation. Numerous research studies have looked into the relationship between genetic variants in miRNA genes and CHD susceptibility. This review highlights the recent research work carried out to identify the relationship of miRNA genes polymorphism with the progression and susceptibility of CHD. Such studies could pave the way for the development of personalized strategies for CHD prevention and treatment based on an individual's genetic profile.
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Affiliation(s)
- Khalid Khan
- National Centre of Excellence in Molecular Biology, University of the Punjab, Pakistan
| | - Aakif Khan
- National Centre of Excellence in Molecular Biology, University of the Punjab, Pakistan
| | - Zia Ur Rahman
- University Institute of Medical Laboratory Technology, the University of Lahore, Pakistan
| | - Faisal Khan
- National Centre of Excellence in Molecular Biology, University of the Punjab, Pakistan
| | - Noreen Latief
- National Centre of Excellence in Molecular Biology, University of the Punjab, Pakistan
| | - Numan Fazal
- University Institute of Medical Laboratory Technology, the University of Lahore, Pakistan.
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Wu C, Duan X, Wang X, Wang L. Advances in the role of epigenetics in homocysteine-related diseases. Epigenomics 2023; 15:769-795. [PMID: 37718931 DOI: 10.2217/epi-2023-0207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/19/2023] Open
Abstract
Homocysteine has a wide range of biological effects. However, the specific molecular mechanism of its pathogenicity is still unclear. The diseases induced by hyperhomocysteinemia (HHcy) are called homocysteine-related diseases. Clinical treatment of HHcy is mainly through folic acid and B-complex vitamins, which are not effective in reducing the associated end point events. Epigenetics is the alteration of heritable genes caused by DNA methylation, histone modification, noncoding RNAs and chromatin remodeling without altering the DNA sequence. In recent years the role of epigenetics in homocysteine-associated diseases has been gradually discovered. This article summarizes the latest evidence on the role of epigenetics in HHcy, providing new directions for its prevention and treatment.
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Affiliation(s)
- Chengyan Wu
- The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China
| | - Xulei Duan
- The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China
| | - Xuehui Wang
- The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China
| | - Libo Wang
- The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China
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Epigenetic Regulation by microRNAs in Hyperhomocysteinemia-Accelerated Atherosclerosis. Int J Mol Sci 2022; 23:ijms232012452. [PMID: 36293305 PMCID: PMC9604464 DOI: 10.3390/ijms232012452] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 10/13/2022] [Accepted: 10/14/2022] [Indexed: 11/16/2022] Open
Abstract
Increased serum levels of homocysteine (Hcy) is a risk factor for cardiovascular disease and is specifically linked to various diseases of the vasculature such as atherosclerosis. However, the precise mechanisms by which Hcy contributes to this condition remain elusive. During the development of atherosclerosis, epigenetic modifications influence gene expression. As such, epigenetic modifications are an adaptive response to endogenous and exogenous factors that lead to altered gene expression by methylation and acetylation reactions of different substrates and the action of noncoding RNA including microRNAs (miRNAs). Epigenetic remodeling modulates cell biology in both physiological and physiopathological conditions. DNA and histone modification have been identified to have a crucial role in the progression of atherosclerosis. However, the potential role of miRNAs in hyperHcy (HHcy)-related atherosclerosis disease remains poorly explored and might be essential as well. There is no review available yet summarizing the contribution of miRNAs to hyperhomocystein-mediated atherogenicity or their potential as therapeutic targets even though their important role has been described in numerous studies. Specifically, downregulation of miR-143 or miR-125b has been shown to regulate VSCMs proliferation in vitro. In preclinical studies, downregulation of miR-92 or miR195-3p has been shown to increase the accumulation of cholesterol in foam cells and increase macrophage inflammation and atherosclerotic plaque formation, respectively. Another preclinical study found that there is a reciprocal regulation between miR-148a/152 and DNMT1 in Hcy-accelerated atherosclerosis. Interestingly, a couple of studies have shown that miR-143 or miR-217 may be used as potential biomarkers in patients with HHcy that may develop atherosclerosis. Moreover, the current review will also update current knowledge on miRNA-based therapies, their challenges, and approaches to deal with Hcy-induced atherosclerosis.
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Chen X, Luo J, Liu J, Chen T, Sun J, Zhang Y, Xi Q. Exploration of the Effect on Genome-Wide DNA Methylation by miR-143 Knock-Out in Mice Liver. Int J Mol Sci 2021; 22:13075. [PMID: 34884879 PMCID: PMC8658369 DOI: 10.3390/ijms222313075] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 11/30/2021] [Accepted: 12/01/2021] [Indexed: 12/12/2022] Open
Abstract
MiR-143 play an important role in hepatocellular carcinoma and liver fibrosis via inhibiting hepatoma cell proliferation. DNA methyltransferase 3 alpha (DNMT3a), as a target of miR-143, regulates the development of primary organic solid tumors through DNA methylation mechanisms. However, the effect of miR-143 on DNA methylation profiles in liver is unclear. In this study, we used Whole-Genome Bisulfite Sequencing (WGBS) to detect the differentially methylated regions (DMRs), and investigated DMR-related genes and their enriched pathways by miR-143. We found that methylated cytosines increased 0.19% in the miR-143 knock-out (KO) liver fed with high-fat diet (HFD), compared with the wild type (WT). Furthermore, compared with the WT group, the CG methylation patterns of the KO group showed lower CG methylation levels in CG islands (CGIs), promoters and hypermethylation in CGI shores, 5'UTRs, exons, introns, 3'UTRs, and repeat regions. A total of 984 DMRs were identified between the WT and KO groups consisting of 559 hypermethylation and 425 hypomethylation DMRs. Furthermore, DMR-related genes were enriched in metabolism pathways such as carbon metabolism (serine hydroxymethyltransferase 2 (Shmt2), acyl-Coenzyme A dehydrogenase medium chain (Acadm)), arginine and proline metabolism (spermine synthase (Sms), proline dehydrogenase (Prodh2)) and purine metabolism (phosphoribosyl pyrophosphate synthetase 2 (Prps2)). In summary, we are the first to report the change in whole-genome methylation levels by miR-143-null through WGBS in mice liver, and provide an experimental basis for clinical diagnosis and treatment in liver diseases, indicating that miR-143 may be a potential therapeutic target and biomarker for liver damage-associated diseases and hepatocellular carcinoma.
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Affiliation(s)
| | | | | | | | | | - Yongliang Zhang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, No. 483 Wushan Road, Guangzhou 510642, China; (X.C.); (J.L.); (J.L.); (T.C.); (J.S.)
| | - Qianyun Xi
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, No. 483 Wushan Road, Guangzhou 510642, China; (X.C.); (J.L.); (J.L.); (T.C.); (J.S.)
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Sui G, Jia L, Song N, Min D, Chen S, Wu Y, Yang G. Aberrant expression of HDL-bound microRNA induced by a high-fat diet in a pig model: implications in the pathogenesis of dyslipidaemia. BMC Cardiovasc Disord 2021; 21:280. [PMID: 34090327 PMCID: PMC8180175 DOI: 10.1186/s12872-021-02084-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Accepted: 05/26/2021] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND A high-fat diet can affect lipid metabolism and trigger cardiovascular diseases. A growing body of studies has revealed the HDL-bound miRNA profiles in familial hypercholesterolaemia; in sharp contrast, relevant studies on high-fat diet-induced dyslipidaemia are lacking. In the current study, HDL-bound miRNAs altered by a high-fat diet were explored to offer some clues for elucidating their effects on the pathogenesis of dyslipidaemia. METHODS Six pigs were randomly divided into two groups of three pigs each, namely, the high-fat diet and the balanced diet groups, which were fed a high-fat diet and balanced diet separately for six months. HDL was separated from plasma, which was followed by dissociation of the miRNA bound to HDL. miRNA sequencing of the isolated miRNA was performed to identify the differential expression profiles between the two groups, which was validated by real-time PCR. TargetScan, miRDB, and miRWalk were used for the prediction of genes targeted by the differential miRNAs. RESULTS Compared with the balanced diet group, the high-fat diet group had significantly higher levels of TG, TC, LDL-C and HDL-C at six months. miRNA sequencing revealed 6 upregulated and 14 downregulated HDL-bound miRNAs in the high-fat diet group compared to the balanced diet group, which was validated by real-time PCR. GO enrichment analysis showed that dysregulated miRNAs in the high-fat diet group were associated with the positive regulation of lipid metabolic processes, positive regulation of lipid biosynthetic processes, and positive regulation of Ras protein signal transduction. Insulin resistance and the Ras signalling pathway were enriched in the KEGG pathway enrichment analysis. CONCLUSIONS Twenty HDL-bound miRNAs are significantly dysregulated in high-fat diet-induced dyslipidaemia. This study presents an analysis of a new set of HDL-bound miRNAs that are altered by a high-fat diet and offers some valuable clues for novel mechanistic insights into high-fat diet-induced dyslipidaemia. Further functional verification study using a larger sample size will be required.
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Affiliation(s)
- Guoyuan Sui
- Key Laboratory of Ministry of Education for Traditional Chinese Medicine Viscera-State Theory and Applications, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, People's Republic of China
| | - Lianqun Jia
- Key Laboratory of Ministry of Education for Traditional Chinese Medicine Viscera-State Theory and Applications, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, People's Republic of China.
| | - Nan Song
- Key Laboratory of Ministry of Education for Traditional Chinese Medicine Viscera-State Theory and Applications, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, People's Republic of China
| | - Dongyu Min
- The Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, People's Republic of China
| | - Si Chen
- Key Laboratory of Ministry of Education for Traditional Chinese Medicine Viscera-State Theory and Applications, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, People's Republic of China
| | - Yao Wu
- Key Laboratory of Ministry of Education for Traditional Chinese Medicine Viscera-State Theory and Applications, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, People's Republic of China
| | - Guanlin Yang
- Key Laboratory of Ministry of Education for Traditional Chinese Medicine Viscera-State Theory and Applications, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, People's Republic of China.
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Golonka RM, Cooper JK, Issa R, Devarasetty PP, Gokula V, Busken J, Zubcevic J, Hill J, Vijay-Kumar M, Menon B, Joe B. Impact of Nutritional Epigenetics in Essential Hypertension: Targeting microRNAs in the Gut-Liver Axis. Curr Hypertens Rep 2021; 23:28. [PMID: 33961141 PMCID: PMC8105193 DOI: 10.1007/s11906-021-01142-9] [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] [Accepted: 03/25/2021] [Indexed: 12/15/2022]
Abstract
PURPOSE OF REVIEW To review the current knowledge on interactions between dietary factors and microRNAs (miRNAs) in essential hypertension (EH) pathogenesis. RECENT FINDINGS There exists an integration of maintenance signals generated by genetic, epigenetic, immune, and environmental (e.g., dietary) factors that work to sustain balance in the gut-liver axis. It is well established that an imbalance in this complex, intertwined system substantially increases the risk for EH. As such, pertinent research has been taken to decipher how each signal operates in isolation and together in EH progression. Recent literature indicates that both macro- and micronutrients interrupt regulatory miRNA expressions and thus, alter multiple cellular processes that contribute to EH and its comorbidities. We highlight how carbohydrates, lipids, proteins, salt, and potassium modify miRNA signatures during EH. The disruption in miRNA expression can negatively impact communication systems such as over activating the renin-angiotensin-aldosterone system, modulating the vascular smooth muscle cell phenotype, and promoting angiogenesis to favor EH. We also delineate the prognostic value of miRNAs in EH and discuss the pros and cons of surgical vs dietary prophylactic approaches in EH prevention. We propose that dietary-dependent perturbation of the miRNA profile is one mechanism within the gut-liver axis that dictates EH development.
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Affiliation(s)
- Rachel M Golonka
- Microbiome Consortium, Center for Hypertension and Precision Medicine, Department of Physiology and Pharmacology, The University of Toledo College of Medicine and Life Sciences, Block Health Science Bldg, 3000 Arlington Ave, Toledo, OH, 43614, USA
| | | | - Rochell Issa
- The University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | | | - Veda Gokula
- The University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Joshua Busken
- The University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Jasenka Zubcevic
- Microbiome Consortium, Center for Hypertension and Precision Medicine, Department of Physiology and Pharmacology, The University of Toledo College of Medicine and Life Sciences, Block Health Science Bldg, 3000 Arlington Ave, Toledo, OH, 43614, USA
- Department of Physiological Sciences and Center for Environmental and Human Toxicology, University of Florida Genetics Institute, Interdisciplinary Program in Biomedical Sciences Neuroscience, College of Veterinary Medicine, University of Florida, Gainesville, FL, 32611, USA
| | - Jennifer Hill
- Microbiome Consortium, Center for Hypertension and Precision Medicine, Department of Physiology and Pharmacology, The University of Toledo College of Medicine and Life Sciences, Block Health Science Bldg, 3000 Arlington Ave, Toledo, OH, 43614, USA
| | - Matam Vijay-Kumar
- Microbiome Consortium, Center for Hypertension and Precision Medicine, Department of Physiology and Pharmacology, The University of Toledo College of Medicine and Life Sciences, Block Health Science Bldg, 3000 Arlington Ave, Toledo, OH, 43614, USA
| | - Bindu Menon
- Department of Medical Education, University of Toledo College of Medicine and Life Sciences, Room 3105B, CCE Bldg, 2920 Arlington Ave, Toledo, OH, 43614, USA.
| | - Bina Joe
- Microbiome Consortium, Center for Hypertension and Precision Medicine, Department of Physiology and Pharmacology, The University of Toledo College of Medicine and Life Sciences, Block Health Science Bldg, 3000 Arlington Ave, Toledo, OH, 43614, USA.
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Yang X, Yang Y, Guo J, Meng Y, Li M, Yang P, Liu X, Aung LHH, Yu T, Li Y. Targeting the epigenome in in-stent restenosis: from mechanisms to therapy. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 23:1136-1160. [PMID: 33664994 PMCID: PMC7896131 DOI: 10.1016/j.omtn.2021.01.024] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Coronary artery disease (CAD) is one of the most common causes of death worldwide. The introduction of percutaneous revascularization has revolutionized the therapy of patients with CAD. Despite the advent of drug-eluting stents, restenosis remains the main challenge in treating patients with CAD. In-stent restenosis (ISR) indicates the reduction in lumen diameter after percutaneous coronary intervention, in which the vessel's lumen re-narrowing is attributed to the aberrant proliferation and migration of vascular smooth muscle cells (VSMCs) and dysregulation of endothelial cells (ECs). Increasing evidence has demonstrated that epigenetics is involved in the occurrence and progression of ISR. In this review, we provide the latest and comprehensive analysis of three separate but related epigenetic mechanisms regulating ISR, namely, DNA methylation, histone modification, and non-coding RNAs. Initially, we discuss the mechanism of restenosis. Furthermore, we discuss the biological mechanism underlying the diverse epigenetic modifications modulating gene expression and functions of VSMCs, as well as ECs in ISR. Finally, we discuss potential therapeutic targets of the small molecule inhibitors of cardiovascular epigenetic factors. A more detailed understanding of epigenetic regulation is essential for elucidating this complex biological process, which will assist in developing and improving ISR therapy.
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Affiliation(s)
- Xi Yang
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Road No. 59 Haier, Qingdao 266100, Shandong, People’s Republic of China
| | - Yanyan Yang
- Department of Immunology, School of Basic Medicine, Qingdao University, No. 308 Ningxia Road, Qingdao 266071, People’s Republic of China
| | - Junjie Guo
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Road No. 59 Haier, Qingdao 266100, Shandong, People’s Republic of China
| | - Yuanyuan Meng
- Department of Cardiac Ultrasound, The Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao 266000, People’s Republic of China
| | - Min Li
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, No. 38 Dengzhou Road, Qingdao 266021, People’s Republic of China
| | - Panyu Yang
- Department of Cardiac Ultrasound, The Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao 266000, People’s Republic of China
| | - Xin Liu
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Road No. 59 Haier, Qingdao 266100, Shandong, People’s Republic of China
| | - Lynn Htet Htet Aung
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, No. 38 Dengzhou Road, Qingdao 266021, People’s Republic of China
| | - Tao Yu
- Department of Cardiac Ultrasound, The Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao 266000, People’s Republic of China
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, No. 38 Dengzhou Road, Qingdao 266021, People’s Republic of China
| | - Yonghong Li
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Road No. 59 Haier, Qingdao 266100, Shandong, People’s Republic of China
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Han X, Liu D, Zhou Y, Wang L, Hou H, Chen H, Zhang L, Chen W, Li X, Zhao L. The negative feedback between miR-143 and DNMT3A regulates cisplatin resistance in ovarian cancer. Cell Biol Int 2021; 45:227-237. [PMID: 33090550 DOI: 10.1002/cbin.11486] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 09/29/2020] [Accepted: 10/13/2020] [Indexed: 12/25/2022]
Abstract
Emerging evidence suggests that miR-143 plays an important role in the regulation of tumor sensitivity to chemotherapeutic agents. The study explores the underlying mechanism of miR-143 in reversing cisplatin resistance in ovarian cancer. The cisplatin-resistant ovarian cancer cell line A2780/CDDP was induced and established via treating A2780 cells by gradually increasing cisplatin concentrations. The IC50 values of A2780/CDDP and A2780 to cisplatin were 218.10 ± 1.12 and 21.99 ± 1.12 μM, respectively. Quantitative real-time polymerase chain reaction (qRT-PCR) results showed that miR-143 was significantly decreased in A2780/CDDP cells compared with A2780 cells. miR-143 overexpression decreased cisplatin resistance in A2780/CDDP, and miR-143 inhibition decreased A2780 sensitivity to cisplatin. Results of qRT-PCR, Western blot analysis, and luciferase reporter assay indicated that the direct target of miR-143 was DNMT3A, which, in turn, was upregulated in A2780/CDDP. DNMT3A overexpression antagonized the sensitizing effect of miR-143 on A2780/CDDP to cisplatin. Knocking down of DNMT3A reduced cisplatin resistance in A2780/CDDP, while overexpression of DNMT3A increased cisplatin resistance in A2780. Methylation-specific polymerase chain reaction results showed that the methylation level in the promoter region of the miR-143 precursor gene was higher in A2780/CDDP cells than in A2780 cells. DNMT3A mediated the hypermethylation of the miR-143 precursor gene, resulting in miR-143 downregulation in A2780/CDDP. miR-143 inhibited cell growth of A2780/CDDP cell in nude mice. Our findings indicated the negative feedback between miR-143 and DNMT3A as a crucial epigenetic modifier of cisplatin resistance in ovarian cancer.
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Affiliation(s)
- Xi Han
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
- Department of Obstetrics and Gynecology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi, China
| | - Dan Liu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Yuanyuan Zhou
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Lijie Wang
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
- Department of Obstetrics and Gynecology, Lanzhou University Second Hospital, Lan Zhou, Shaanxi, China
| | - Huilian Hou
- Department of Pathology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - He Chen
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
- Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Lirui Zhang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Wei Chen
- Center for Laboratory Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Xu Li
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
- Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Le Zhao
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
- Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
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11
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Tao J, Xia L, Cai Z, Liang L, Chen Y, Meng J, Wang Z. Interaction Between microRNA and DNA Methylation in Atherosclerosis. DNA Cell Biol 2020; 40:101-115. [PMID: 33259723 DOI: 10.1089/dna.2020.6138] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Atherosclerosis (AS) is a chronic inflammatory disease accompanied by complex pathological changes, such as endothelial dysfunction, foam cell formation, and vascular smooth muscle cell proliferation. Many approaches, including regulating AS-related gene expression in the transcriptional or post-transcriptional level, contribute to alleviating AS development. The DNA methylation is a crucial epigenetic modification in regulating cell function by silencing the relative gene expression. The microRNA (miRNA) is a type of noncoding RNA that plays an important role in gene post-transcriptional regulation and disease development. The DNA methylation and the miRNA are important epigenetic factors in AS. However, recent studies have found a mutual regulation between these two factors in AS development. In this study, recent insights into the roles of miRNA and DNA methylation and their interaction in the AS progression are reviewed.
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Affiliation(s)
- Jun Tao
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical College, University of South China, Hengyang, China
| | - Linzhen Xia
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical College, University of South China, Hengyang, China
| | - Zemin Cai
- Department of Pediatrics and The First Affiliated Hospital of University of South China, Hengyang, China
| | - Lingli Liang
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical College, University of South China, Hengyang, China
| | - Yanjun Chen
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical College, University of South China, Hengyang, China
| | - Jun Meng
- Functional Department, The First Affiliated Hospital of University of South China, Hengyang, China
| | - Zuo Wang
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical College, University of South China, Hengyang, China
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12
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Rapp N, Evenepoel P, Stenvinkel P, Schurgers L. Uremic Toxins and Vascular Calcification-Missing the Forest for All the Trees. Toxins (Basel) 2020; 12:E624. [PMID: 33003628 PMCID: PMC7599869 DOI: 10.3390/toxins12100624] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 09/22/2020] [Accepted: 09/25/2020] [Indexed: 12/23/2022] Open
Abstract
The cardiorenal syndrome relates to the detrimental interplay between the vascular system and the kidney. The uremic milieu induced by reduced kidney function alters the phenotype of vascular smooth muscle cells (VSMC) and promotes vascular calcification, a condition which is strongly linked to cardiovascular morbidity and mortality. Biological mechanisms involved include generation of reactive oxygen species, inflammation and accelerated senescence. A better understanding of the vasotoxic effects of uremic retention molecules may reveal novel avenues to reduce vascular calcification in CKD. The present review aims to present a state of the art on the role of uremic toxins in pathogenesis of vascular calcification. Evidence, so far, is fragmentary and limited with only a few uremic toxins being investigated, often by a single group of investigators. Experimental heterogeneity furthermore hampers comparison. There is a clear need for a concerted action harmonizing and standardizing experimental protocols and combining efforts of basic and clinical researchers to solve the complex puzzle of uremic vascular calcification.
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MESH Headings
- Animals
- Cardio-Renal Syndrome/metabolism
- Cardio-Renal Syndrome/pathology
- Cardio-Renal Syndrome/physiopathology
- Cardio-Renal Syndrome/therapy
- Humans
- Kidney/metabolism
- Kidney/pathology
- Kidney/physiopathology
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Muscle, Smooth, Vascular/physiopathology
- Prognosis
- Renal Insufficiency, Chronic/metabolism
- Renal Insufficiency, Chronic/pathology
- Renal Insufficiency, Chronic/physiopathology
- Renal Insufficiency, Chronic/therapy
- Toxins, Biological/metabolism
- Uremia/metabolism
- Uremia/pathology
- Uremia/physiopathology
- Uremia/therapy
- Vascular Calcification/metabolism
- Vascular Calcification/pathology
- Vascular Calcification/physiopathology
- Vascular Calcification/therapy
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Affiliation(s)
- Nikolas Rapp
- Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, 6229 ER Maastricht, The Netherlands;
| | - Pieter Evenepoel
- Laboratory of Nephrology, KU Leuven Department of Microbiology and Immunology, University Hospitals Leuven, 3000 Leuven, Belgium;
| | - Peter Stenvinkel
- Karolinska Institute, Department of Clinical Science, Intervention and Technology, Division of Renal Medicine, 141 86 Stockholm, Sweden;
| | - Leon Schurgers
- Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, 6229 ER Maastricht, The Netherlands;
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13
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Nabipoorashrafi SA, Shomali N, Sadat-Hatamnezhad L, Mahami-Oskouei M, Mahmoudi J, Sandoghchian Shotorbani B, Akbari M, Xu H, Sandoghchian Shotorbani S. miR-143 acts as an inhibitor of migration and proliferation as well as an inducer of apoptosis in melanoma cancer cells in vitro. IUBMB Life 2020; 72:2034-2044. [PMID: 32687246 DOI: 10.1002/iub.2345] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 06/11/2020] [Accepted: 06/12/2020] [Indexed: 12/20/2022]
Abstract
Melanoma is a serious form of skin cancers begins in the melanocyte. Micro-RNAs are small noncoding RNA with 19 to 25 nucleotides in length involves in the regulation of a wide range of biological processes. MicroRNAs are affected by an aberrant epigenetic alteration in the tumors that may lead to their dysregulation and formation of cancer. Recently, dysregulation of numerous microRNAs has been reported in different types of cancer. The present study focused on the role of miR-143 in carcinogenesis of melanoma cancer. Here, we evaluated the expression level of miR-143 in three melanoma cell lines in comparison with the normal human epidermal melanocyte cell line. Then, miR-143 gene plasmid transfected into the WM115 cell line, for having the lowest expression of miR-143. In addition, the effect of miR-143 transfection on mRNA and protein levels of metastasis-related genes was performed along with MTT assay, wound healing assay, and flow cytometry. The results showed that mRNA and protein expression levels of metastasis-related genes including MMP-9, E-cadherin, Vimentin, and CXCR4 have been reduced following transfection of miR-143. Moreover, the results of the scratch test showed that miR-143 re-expression inhibited cell migration. Also, the role of miR-143 in the induction of apoptosis and inhibition of proliferation by flow cytometry and MTT was confirmed. As a result, the present study showed that miR-143 was involved in metastatic and apoptotic pathways, suggesting that miR-143 acts as a tumor-suppressor microRNA in melanoma cancer.
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Affiliation(s)
| | - Navid Shomali
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | | | - Javad Mahmoudi
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Morteza Akbari
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Huaxi Xu
- Department of Immunology, Jiangsu University of Medical Sciences, Zhenjiang, China
| | - Siamak Sandoghchian Shotorbani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Jiangsu University of Medical Sciences, Zhenjiang, China
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14
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Rajić J, Dinić S, Uskoković A, Arambašić Jovanović J, Tolić A, Đorđević M, Đorđević M, Poznanović G, Mihailović M, Inic-Kanada A, Barisani-Asenbauer T, Grdović N, Vidaković M. DNA methylation of miR-200 clusters promotes epithelial to mesenchymal transition in human conjunctival epithelial cells. Exp Eye Res 2020; 197:108047. [PMID: 32387379 DOI: 10.1016/j.exer.2020.108047] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 04/17/2020] [Accepted: 04/27/2020] [Indexed: 01/09/2023]
Abstract
Epithelial to mesenchymal transition (EMT) contributes to fibrosis associated pathologies including scarring of different ocular tissues. Recently targeting EMT is seen as an appropriate therapeutic approach for different fibrosis related eye diseases such as macular degeneration or glaucoma surgery related fibrosis. Nevertheless, for ocular surface diseases, target genes specific for particular cell type or condition are still undefined. This study aimed to expose the complex regulatory mechanisms that trigger EMT in human conjunctival epithelial (HCjE) cells. EMT was induced by prolonged treatment with two TGF-β isoforms, TGF-β1 and TGF-β2, and their combination. TGF-β1 showed the strongest potential for initiating EMT in HCjE cells, reflected on morphological changes, cell migration and the levels of mRNA expression of different epithelial (CDH1, OCLN, DSP) and mesenchymal (CDH2, FN1, VIM, SNAI1, ZEB2, TWIST1) marker genes. Co-treatment with the DNA demethylating agent 5-Azacytidine (5-AzaC) was capable of stopping the transition of HCjE cells towards a mesenchymal phenotype, based on morphological features, reduced cell mobility and mRNA and protein expression levels of epithelial and mesenchymal marker genes. An EMT qRT-PCR-based array revealed that EMT induced considerable alterations in gene expression, with downregulation of the majority of epithelial marker genes and upregulation of genes specific for the mesenchymal state. The major effect of 5-AzaC treatment was observed as a suppression of mesenchymal marker genes, suggesting the involvement of upstream negative regulator(s) whose promoter demethylation and subsequent expression will in turn promote EMT switch off. The expression level of miRNAs potentially important for EMT induction was determined using qRT-PCR-based array which pointed at members of miR-200 family as main regulators of EMT process in HCjE cells. 5-AzaC treatment induced increased expression of miR-200a, -200b, -200c and miR-141 towards the control level, indicating important role of DNA methylation in their regulation. The DNA methylation status of both miR-200 family clusters, analyzed with high-resolution melting (HRM) and bisulfite sequencing (Bis-Seq), revealed that TGF-β1-induced EMT was accompanied by increase in promoter CpG methylation of both miR-200 loci, which was reverted after 5-AzaC treatment. In conclusion, our results indicate that DNA demethylation of promoters of miR-200 loci is critically important for stopping and reverting the EMT in human conjunctival epithelial cells, suggesting the potential for the development of novel epigenetic-based therapeutic strategies for treating conjunctival conditions associated with EMT.
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Affiliation(s)
- Jovana Rajić
- Department of Molecular Biology, Institute for Biological Research "Siniša Stanković", National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11060, Belgrade, Serbia
| | - Svetlana Dinić
- Department of Molecular Biology, Institute for Biological Research "Siniša Stanković", National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11060, Belgrade, Serbia
| | - Aleksandra Uskoković
- Department of Molecular Biology, Institute for Biological Research "Siniša Stanković", National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11060, Belgrade, Serbia
| | - Jelena Arambašić Jovanović
- Department of Molecular Biology, Institute for Biological Research "Siniša Stanković", National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11060, Belgrade, Serbia
| | - Anja Tolić
- Department of Molecular Biology, Institute for Biological Research "Siniša Stanković", National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11060, Belgrade, Serbia
| | - Marija Đorđević
- Department of Molecular Biology, Institute for Biological Research "Siniša Stanković", National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11060, Belgrade, Serbia
| | - Miloš Đorđević
- Department of Molecular Biology, Institute for Biological Research "Siniša Stanković", National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11060, Belgrade, Serbia
| | - Goran Poznanović
- Department of Molecular Biology, Institute for Biological Research "Siniša Stanković", National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11060, Belgrade, Serbia
| | - Mirjana Mihailović
- Department of Molecular Biology, Institute for Biological Research "Siniša Stanković", National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11060, Belgrade, Serbia
| | - Aleksandra Inic-Kanada
- Institute of Specific Prophylaxis and Tropical Medicine, Medical University of Vienna, Kinderspitalgasse 15, 1090, Vienna, Austria
| | - Talin Barisani-Asenbauer
- OCUVAC - Center of Ocular Inflammation and Infection, Laura Bassi Centres of Expertise, Medical University of Vienna, Kinderspitalgasse 15, 1090, Vienna, Austria.
| | - Nevena Grdović
- Department of Molecular Biology, Institute for Biological Research "Siniša Stanković", National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11060, Belgrade, Serbia.
| | - Melita Vidaković
- Department of Molecular Biology, Institute for Biological Research "Siniša Stanković", National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11060, Belgrade, Serbia
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15
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Roles of Histone Acetylation Modifiers and Other Epigenetic Regulators in Vascular Calcification. Int J Mol Sci 2020; 21:ijms21093246. [PMID: 32375326 PMCID: PMC7247359 DOI: 10.3390/ijms21093246] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 04/28/2020] [Accepted: 05/01/2020] [Indexed: 02/07/2023] Open
Abstract
Vascular calcification (VC) is characterized by calcium deposition inside arteries and is closely associated with the morbidity and mortality of atherosclerosis, chronic kidney disease, diabetes, and other cardiovascular diseases (CVDs). VC is now widely known to be an active process occurring in vascular smooth muscle cells (VSMCs) involving multiple mechanisms and factors. These mechanisms share features with the process of bone formation, since the phenotype switching from the contractile to the osteochondrogenic phenotype also occurs in VSMCs during VC. In addition, VC can be regulated by epigenetic factors, including DNA methylation, histone modification, and noncoding RNAs. Although VC is commonly observed in patients with chronic kidney disease and CVD, specific drugs for VC have not been developed. Thus, discovering novel therapeutic targets may be necessary. In this review, we summarize the current experimental evidence regarding the role of epigenetic regulators including histone deacetylases and propose the therapeutic implication of these regulators in the treatment of VC.
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16
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Candidate SNP Markers of Atherogenesis Significantly Shifting the Affinity of TATA-Binding Protein for Human Gene Promoters show stabilizing Natural Selection as a Sum of Neutral Drift Accelerating Atherogenesis and Directional Natural Selection Slowing It. Int J Mol Sci 2020; 21:ijms21031045. [PMID: 32033288 PMCID: PMC7037642 DOI: 10.3390/ijms21031045] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 02/03/2020] [Accepted: 02/04/2020] [Indexed: 12/15/2022] Open
Abstract
(1) Background: The World Health Organization (WHO) regards atherosclerosis-related myocardial infarction and stroke as the main causes of death in humans. Susceptibility to atherogenesis-associated diseases is caused by single-nucleotide polymorphisms (SNPs). (2) Methods: Using our previously developed public web-service SNP_TATA_Comparator, we estimated statistical significance of the SNP-caused alterations in TATA-binding protein (TBP) binding affinity for 70 bp proximal promoter regions of the human genes clinically associated with diseases syntonic or dystonic with atherogenesis. Additionally, we did the same for several genes related to the maintenance of mitochondrial genome integrity, according to present-day active research aimed at retarding atherogenesis. (3) Results: In dbSNP, we found 1186 SNPs altering such affinity to the same extent as clinical SNP markers do (as estimated). Particularly, clinical SNP marker rs2276109 can prevent autoimmune diseases via reduced TBP affinity for the human MMP12 gene promoter and therefore macrophage elastase deficiency, which is a well-known physiological marker of accelerated atherogenesis that could be retarded nutritionally using dairy fermented by lactobacilli. (4) Conclusions: Our results uncovered SNPs near clinical SNP markers as the basis of neutral drift accelerating atherogenesis and SNPs of genes encoding proteins related to mitochondrial genome integrity and microRNA genes associated with instability of the atherosclerotic plaque as a basis of directional natural selection slowing atherogenesis. Their sum may be stabilizing the natural selection that sets the normal level of atherogenesis.
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17
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Inflammation‐regulatory microRNAs: Valuable targets for intracranial atherosclerosis. J Neurosci Res 2019; 97:1242-1252. [DOI: 10.1002/jnr.24487] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 05/24/2019] [Accepted: 06/10/2019] [Indexed: 12/16/2022]
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18
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Dysregulation of Epigenetic Mechanisms of Gene Expression in the Pathologies of Hyperhomocysteinemia. Int J Mol Sci 2019; 20:ijms20133140. [PMID: 31252610 PMCID: PMC6651274 DOI: 10.3390/ijms20133140] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Revised: 06/21/2019] [Accepted: 06/25/2019] [Indexed: 02/07/2023] Open
Abstract
Hyperhomocysteinemia (HHcy) exerts a wide range of biological effects and is associated with a number of diseases, including cardiovascular disease, dementia, neural tube defects, and cancer. Although mechanisms of HHcy toxicity are not fully uncovered, there has been a significant progress in their understanding. The picture emerging from the studies of homocysteine (Hcy) metabolism and pathophysiology is a complex one, as Hcy and its metabolites affect biomolecules and processes in a tissue- and sex-specific manner. Because of their connection to one carbon metabolism and editing mechanisms in protein biosynthesis, Hcy and its metabolites impair epigenetic control of gene expression mediated by DNA methylation, histone modifications, and non-coding RNA, which underlies the pathology of human disease. In this review we summarize the recent evidence showing that epigenetic dysregulation of gene expression, mediated by changes in DNA methylation and histone N-homocysteinylation, is a pathogenic consequence of HHcy in many human diseases. These findings provide new insights into the mechanisms of human disease induced by Hcy and its metabolites, and suggest therapeutic targets for the prevention and/or treatment.
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19
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Xu S, Kamato D, Little PJ, Nakagawa S, Pelisek J, Jin ZG. Targeting epigenetics and non-coding RNAs in atherosclerosis: from mechanisms to therapeutics. Pharmacol Ther 2019; 196:15-43. [PMID: 30439455 PMCID: PMC6450782 DOI: 10.1016/j.pharmthera.2018.11.003] [Citation(s) in RCA: 120] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Atherosclerosis, the principal cause of cardiovascular death worldwide, is a pathological disease characterized by fibro-proliferation, chronic inflammation, lipid accumulation, and immune disorder in the vessel wall. As the atheromatous plaques develop into advanced stage, the vulnerable plaques are prone to rupture, which causes acute cardiovascular events, including ischemic stroke and myocardial infarction. Emerging evidence has suggested that atherosclerosis is also an epigenetic disease with the interplay of multiple epigenetic mechanisms. The epigenetic basis of atherosclerosis has transformed our knowledge of epigenetics from an important biological phenomenon to a burgeoning field in cardiovascular research. Here, we provide a systematic and up-to-date overview of the current knowledge of three distinct but interrelated epigenetic processes (including DNA methylation, histone methylation/acetylation, and non-coding RNAs), in atherosclerotic plaque development and instability. Mechanistic and conceptual advances in understanding the biological roles of various epigenetic modifiers in regulating gene expression and functions of endothelial cells (vascular homeostasis, leukocyte adhesion, endothelial-mesenchymal transition, angiogenesis, and mechanotransduction), smooth muscle cells (proliferation, migration, inflammation, hypertrophy, and phenotypic switch), and macrophages (differentiation, inflammation, foam cell formation, and polarization) are discussed. The inherently dynamic nature and reversibility of epigenetic regulation, enables the possibility of epigenetic therapy by targeting epigenetic "writers", "readers", and "erasers". Several Food Drug Administration-approved small-molecule epigenetic drugs show promise in pre-clinical studies for the treatment of atherosclerosis. Finally, we discuss potential therapeutic implications and challenges for future research involving cardiovascular epigenetics, with an aim to provide a translational perspective for identifying novel biomarkers of atherosclerosis, and transforming precision cardiovascular research and disease therapy in modern era of epigenetics.
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Affiliation(s)
- Suowen Xu
- Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
| | - Danielle Kamato
- School of Pharmacy, The University of Queensland, Wooloongabba, QLD 4102, Australia; Department of Pharmacy, Xinhua College of Sun Yat-sen University, Guangzhou 510520, China
| | - Peter J Little
- School of Pharmacy, The University of Queensland, Wooloongabba, QLD 4102, Australia; Department of Pharmacy, Xinhua College of Sun Yat-sen University, Guangzhou 510520, China
| | - Shinichi Nakagawa
- RNA Biology Laboratory, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12-jo Nishi 6-chome, Kita-ku, Sapporo 060-0812, Japan
| | - Jaroslav Pelisek
- Department of Vascular and Endovascular Surgery, Klinikum rechts der Isar der Technischen Universitaet Muenchen, Germany
| | - Zheng Gen Jin
- Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
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20
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Djuric D, Jakovljevic V, Zivkovic V, Srejovic I. Homocysteine and homocysteine-related compounds: an overview of the roles in the pathology of the cardiovascular and nervous systems. Can J Physiol Pharmacol 2018; 96:991-1003. [PMID: 30130426 DOI: 10.1139/cjpp-2018-0112] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Homocysteine, an amino acid containing a sulfhydryl group, is an intermediate product during metabolism of the amino acids methionine and cysteine. Hyperhomocysteinemia is used as a predictive risk factor for cardiovascular disorders, the stroke progression, screening for inborn errors of methionine metabolism, and as a supplementary test for vitamin B12 deficiency. Two organic systems in which homocysteine has the most harmful effects are the cardiovascular and nervous system. The adverse effects of homocysteine are achieved by the action of several different mechanisms, such as overactivation of N-methyl-d-aspartate receptors, activation of Toll-like receptor 4, disturbance in Ca2+ handling, increased activity of nicotinamide adenine dinucleotide phosphate-oxidase and subsequent increase of production of reactive oxygen species, increased activity of nitric oxide synthase and nitric oxide synthase uncoupling and consequent impairment in nitric oxide and reactive oxygen species synthesis. Increased production of reactive species during hyperhomocysteinemia is related with increased expression of several proinflammatory cytokines, including IL-1β, IL-6, TNF-α, MCP-1, and intracellular adhesion molecule-1. All these mechanisms contribute to the emergence of diseases like atherosclerosis and related complications such as myocardial infarction, stroke, aortic aneurysm, as well as Alzheimer disease and epilepsy. This review provides evidence that supports the causal role for hyperhomocysteinemia in the development of cardiovascular disease and nervous system disorders.
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Affiliation(s)
- Dragan Djuric
- a Institute of Medical Physiology "Richard Burian" Faculty of Medicine, University of Belgrade, Visegradska 26, Belgrade 11000, Serbia
| | - Vladimir Jakovljevic
- b Department of Physiology, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, Kragujevac 34000, Serbia.,c Department of Human Pathology, I.M. Sechenov First Moscow State Medical University (Sechenov University), Trubetskaya st. 8, Moscow 119991, Russia
| | - Vladimir Zivkovic
- b Department of Physiology, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, Kragujevac 34000, Serbia
| | - Ivan Srejovic
- b Department of Physiology, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, Kragujevac 34000, Serbia
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21
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Lin X, Xu F, Cui RR, Xiong D, Zhong JY, Zhu T, Li F, Wu F, Xie XB, Mao MZ, Liao XB, Yuan LQ. Arterial Calcification Is Regulated Via an miR-204/DNMT3a Regulatory Circuit Both In Vitro and in Female Mice. Endocrinology 2018; 159:2905-2916. [PMID: 29850805 DOI: 10.1210/en.2018-00320] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Accepted: 05/24/2018] [Indexed: 12/16/2022]
Abstract
Arterial calcification is a common cardiovascular disease that initiates from a process of osteoblastic differentiation of vascular smooth muscle cells (VSMCs). Accumulating evidence has demonstrated that microRNAs play an important role in regulating arterial calcification. miR-204 was significantly downregulated in calcified human renal arteries from patients with uremia; calcified arteries of mice, due to 5/6 nephrectomy with a high-phosphate diet (5/6 NTP); and in VSMCs induced by high phosphate concentration. The overexpression of miR-204 alleviated the osteoblastic differentiation of VSMCs. Bisulphite sequencing PCR revealed that CpG sites upstream of miR-204 DNA were hypermethylated in calcified VSMCs; in calcified arteries of mice, due to 5/6 NTP; and in calcified renal artery tissues from patients with uremia. Moreover, increased DNMT3a resulted in the hypermethylation of miR-204 in high phosphate concentration-induced VSMCs, whereas 5-aza-2'-deoxycytidine could restore the expression of miR-204 in high phosphate concentration-induced VSMCs. Moreover, we found that DNMT3a was the target of miR-204, and the methylation ratio of miR-204 was decreased significantly, meaning that the expression of miR-204 was restored when DNMT3a was knocked down by using DNMT3a small interfering RNA, resulting in abrogation of the effect of high phosphate concentration on VSMC calcification. The progress of arterial calcification is regulated by the miR-204/DNMT3a regulatory circuit.
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Affiliation(s)
- Xiao Lin
- Department of Endocrinology and Metabolism, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, National Clinical Research Center for Metabolic Diseases, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, People's Republic of China
- Department of Geriatrics, Institute of Aging and Geriatrics, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Feng Xu
- Department of Endocrinology and Metabolism, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, National Clinical Research Center for Metabolic Diseases, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Rong-Rong Cui
- Department of Endocrinology and Metabolism, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, National Clinical Research Center for Metabolic Diseases, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Dan Xiong
- Department of Endocrinology and Metabolism, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, National Clinical Research Center for Metabolic Diseases, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Jia-Yu Zhong
- Department of Endocrinology and Metabolism, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, National Clinical Research Center for Metabolic Diseases, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Ting Zhu
- Department of Endocrinology and Metabolism, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, National Clinical Research Center for Metabolic Diseases, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Fuxingzi Li
- Department of Endocrinology and Metabolism, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, National Clinical Research Center for Metabolic Diseases, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Feng Wu
- Department of Pathology, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Xu-Biao Xie
- Center of Organ Transplantation, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Min-Zhi Mao
- Department of Orthopedics, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Xiao-Bo Liao
- Department of Cardiovascular Surgery, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Ling-Qing Yuan
- Department of Endocrinology and Metabolism, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, National Clinical Research Center for Metabolic Diseases, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, People's Republic of China
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22
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MicroRNA-143 targets ERK5 in granulopoiesis and predicts outcome of patients with acute myeloid leukemia. Cell Death Dis 2018; 9:814. [PMID: 30050105 PMCID: PMC6062564 DOI: 10.1038/s41419-018-0837-x] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Revised: 05/30/2018] [Accepted: 06/26/2018] [Indexed: 12/12/2022]
Abstract
Hematopoiesis, the formation of blood cells from hematopoietic stem cells (HSC), is a highly regulated process. Since the discovery of microRNAs (miRNAs), several studies have shown their significant role in the regulation of the hematopoietic system. Impaired expression of miRNAs leads to disrupted cellular pathways and in particular causes loss of hematopoietic ability. Here, we report a previously unrecognized function of miR-143 in granulopoiesis. Hematopoietic cells undergoing granulocytic differentiation exhibited increased miR-143 expression. Overexpression or ablation of miR-143 expression resulted in accelerated granulocytic differentiation or block of differentiation, respectively. The absence of miR-143 in mice resulted in a reduced number of mature granulocytes in blood and bone marrow. Additionally, we observed an association of high miR-143 expression levels with a higher probability of survival in two different cohorts of patients with acute myeloid leukemia (AML). Overexpression of miR-143 in AML cells impaired cell growth, partially induced differentiation, and caused apoptosis. Argonaute2-RNA-Immunoprecipitation assay revealed ERK5, a member of the MAPK-family, as a target of miR-143 in myeloid cells. Further, we observed an inverse correlation of miR-143 and ERK5 in primary AML patient samples, and in CD34+ HSPCs undergoing granulocytic differentiation and we confirmed functional relevance of ERK5 in myeloid cells. In conclusion, our data describe miR-143 as a relevant factor in granulocyte differentiation, whose expression may be useful as a prognostic and therapeutic factor in AML therapy.
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23
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Semina SE, Scherbakov AM, Vnukova AA, Bagrov DV, Evtushenko EG, Safronova VM, Golovina DA, Lyubchenko LN, Gudkova MV, Krasil'nikov MA. Exosome-Mediated Transfer of Cancer Cell Resistance to Antiestrogen Drugs. Molecules 2018; 23:molecules23040829. [PMID: 29617321 PMCID: PMC6017149 DOI: 10.3390/molecules23040829] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Revised: 03/29/2018] [Accepted: 04/02/2018] [Indexed: 12/26/2022] Open
Abstract
Exosomes are small vesicles which are produced by the cells and released into the surrounding space. They can transfer biomolecules into recipient cells. The main goal of the work was to study the exosome involvement in the cell transfer of hormonal resistance. The experiments were performed on in vitro cultured estrogen-dependent MCF-7 breast cancer cells and MCF-7 sublines resistant to SERM tamoxifen and/or biguanide metformin, which exerts its anti-proliferative effect, at least in a part, via the suppression of estrogen machinery. The exosomes were purified by differential ultracentrifugation, cell response to tamoxifen was determined by MTT test, and the level and activity of signaling proteins were determined by Western blot and reporter analysis. We found that the treatment of the parent MCF-7 cells with exosomes from the resistant cells within 14 days lead to the partial resistance of the MCF-7 cells to antiestrogen drugs. The primary resistant cells and the cells with the exosome-induced resistance were characterized with these common features: decrease in ERα activity and parallel activation of Akt and AP-1, NF-κB, and SNAIL1 transcriptional factors. In general, we evaluate the established results as the evidence of the possible exosome involvement in the transferring of the hormone/metformin resistance in breast cancer cells.
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Affiliation(s)
- Svetlana E Semina
- N.N. Blokhin National Medical Research Center of Oncology, Kashirskoye shosse 24, Moscow 115478, Russia.
| | - Alexander M Scherbakov
- N.N. Blokhin National Medical Research Center of Oncology, Kashirskoye shosse 24, Moscow 115478, Russia.
| | - Anna A Vnukova
- Faculty of Preventive Medicine, I.M. Sechenov First Moscow State Medical University, Trubetskaya Street 8-2, Moscow 119991, Russia.
| | - Dmitry V Bagrov
- Faculty of Biology, Lomonosov Moscow State University, 1/12, Leninskie gory, Moscow 119234, Russia.
| | - Evgeniy G Evtushenko
- Faculty of Chemistry, Lomonosov Moscow State University, 1/3, Leninskie gory, Moscow 119234, Russia.
| | - Vera M Safronova
- N.N. Blokhin National Medical Research Center of Oncology, Kashirskoye shosse 24, Moscow 115478, Russia.
| | - Daria A Golovina
- N.N. Blokhin National Medical Research Center of Oncology, Kashirskoye shosse 24, Moscow 115478, Russia.
| | - Ludmila N Lyubchenko
- N.N. Blokhin National Medical Research Center of Oncology, Kashirskoye shosse 24, Moscow 115478, Russia.
| | - Margarita V Gudkova
- N.N. Blokhin National Medical Research Center of Oncology, Kashirskoye shosse 24, Moscow 115478, Russia.
| | - Mikhail A Krasil'nikov
- N.N. Blokhin National Medical Research Center of Oncology, Kashirskoye shosse 24, Moscow 115478, Russia.
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24
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Liu K, Xuekelati S, Zhou K, Yan Z, Yang X, Inayat A, Wu J, Guo X. Expression Profiles of Six Atherosclerosis-Associated microRNAs That Cluster in Patients with Hyperhomocysteinemia: A Clinical Study. DNA Cell Biol 2018; 37:189-198. [PMID: 29461880 DOI: 10.1089/dna.2017.3845] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The aim of this study is to discuss the hypothesis that expression of plasma atherosclerosis-associated microRNAs (miRNAs) in hyperhomocysteinemia (Hhcy) patients could predict the presence of atherosclerosis from different channels. Six plasma miRNAs (miR-145, miR-155, miR-222, miR-133, miR-217, and miR-30) selected for our study have been confirmed as critical gene regulators involved in atherosclerosis and can be steadily determined in plasma. Expression of the above six plasma circulating miRNAs revealed significant upregulation of two miRNAs (miR-133 and miR-217) and downregulation of three miRNAs (miR-145, miR-155, and miR-222). Six candidate miRNAs showed a significant correlation with homocysteine (Hcy) or lipid parameters. The results of this study indicated that miR-217 was further significantly upregulated in Hhcy + ATH groups than in normal control, Hhcy-, and atherosclerosis-alone (ATH) groups and it showed a significant negative correlation with Hcy and triglycerides. More specifically, miR-217 showed the most specific expression patterns in all patients with atherosclerosis (ATH and Hhcy + ATH groups), which may have been a diagnostic value for Hhcy complicated with atherosclerosis, and predicted the progress of atherosclerosis in Hhcy patients effectively.
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Affiliation(s)
- Kejian Liu
- 1 Department of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China .,2 Department of Cardiology, The First Affiliated Hospital, Shihezi University School of Medicine , Shihezi, China
| | - Saiyare Xuekelati
- 3 The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University , Shihezi, China
| | - Kang Zhou
- 2 Department of Cardiology, The First Affiliated Hospital, Shihezi University School of Medicine , Shihezi, China
| | - Zhitao Yan
- 2 Department of Cardiology, The First Affiliated Hospital, Shihezi University School of Medicine , Shihezi, China
| | - Xu Yang
- 2 Department of Cardiology, The First Affiliated Hospital, Shihezi University School of Medicine , Shihezi, China
| | - Azeem Inayat
- 3 The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University , Shihezi, China
| | - Jiangdong Wu
- 3 The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University , Shihezi, China
| | - Xiaomei Guo
- 1 Department of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China
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25
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Tristán-Flores FE, Guzmán P, Ortega-Kermedy MS, Cruz-Torres G, de la Rocha C, Silva-Martínez GA, Rodríguez-Ríos D, Alvarado-Caudillo Y, Barbosa-Sabanero G, Sayols S, Lund G, Zaina S. Liver X Receptor-Binding DNA Motif Associated With Atherosclerosis-Specific DNA Methylation Profiles of Alu Elements and Neighboring CpG Islands. J Am Heart Assoc 2018; 7:e007686. [PMID: 29386205 PMCID: PMC5850253 DOI: 10.1161/jaha.117.007686] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2017] [Accepted: 10/18/2017] [Indexed: 12/21/2022]
Abstract
BACKGROUND The signals that determine atherosclerosis-specific DNA methylation profiles are only partially known. We previously identified a 29-bp DNA motif (differential methylation motif [DMM]) proximal to CpG islands (CGIs) that undergo demethylation in advanced human atheromas. Those data hinted that the DMM docks modifiers of DNA methylation and transcription. METHODS AND RESULTS We sought to functionally characterize the DMM. We showed that the DMM overlaps with the RNA polymerase III-binding B box of Alu short interspersed nuclear elements and contains a DR2 nuclear receptor response element. Pointing to a possible functional role for an Alu DMM, CGIs proximal (<100 bp) to near-intact DMM-harboring Alu are significantly less methylated relative to CGIs proximal to degenerate DMM-harboring Alu or to DMM-devoid mammalian-wide interspersed repeat short interspersed nuclear elements in human arteries. As for DMM-binding factors, LXRB (liver X receptor β) binds the DMM in a DR2-dependent fashion, and LXR (liver X receptor) agonists induce significant hypermethylation of the bulk of Alu in THP-1 cells. Furthermore, we describe 3 intergenic long noncoding RNAs that harbor a DMM, are under transcriptional control by LXR agonists, and are differentially expressed between normal and atherosclerotic human aortas. Notably, CGIs adjacent to those long noncoding RNAs tend to be hypomethylated in symptomatic relative to stable human atheromas. CONCLUSIONS Collectively, the data suggest that a DMM is associated with 2 distinct methylation states: relatively low methylation of in cis CGIs and Alu element hypermethylation. Based on the known atheroprotective role of LXRs, we propose that LXR agonist-induced Alu hypermethylation, a landmark of atherosclerosis, is a compensatory rather than proatherogenic response.
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Affiliation(s)
| | - Plinio Guzmán
- Department of Genetic Engineering, CINVESTAV Irapuato Unit, Irapuato, Gto, Mexico
| | | | - Gabriela Cruz-Torres
- Department of Medical Sciences, Division of Health Sciences, León Campus, University of Guanajuato, León, Gto, Mexico
| | - Carmen de la Rocha
- Department of Genetic Engineering, CINVESTAV Irapuato Unit, Irapuato, Gto, Mexico
| | | | - Dalia Rodríguez-Ríos
- Department of Genetic Engineering, CINVESTAV Irapuato Unit, Irapuato, Gto, Mexico
| | - Yolanda Alvarado-Caudillo
- Department of Medical Sciences, Division of Health Sciences, León Campus, University of Guanajuato, León, Gto, Mexico
| | - Gloria Barbosa-Sabanero
- Department of Medical Sciences, Division of Health Sciences, León Campus, University of Guanajuato, León, Gto, Mexico
| | - Sergi Sayols
- Institute of Molecular Biology gGmbH, Mainz, Germany
| | - Gertrud Lund
- Department of Genetic Engineering, CINVESTAV Irapuato Unit, Irapuato, Gto, Mexico
| | - Silvio Zaina
- Department of Medical Sciences, Division of Health Sciences, León Campus, University of Guanajuato, León, Gto, Mexico
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26
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Zhang JW, Yan R, Tang YS, Guo YZ, Chang Y, Jing L, Wang YL, Zhang JZ. Hyperhomocysteinemia-induced autophagy and apoptosis with downregulation of hairy enhancer of split 1/5 in cortical neurons in mice. Int J Immunopathol Pharmacol 2017; 30:371-382. [PMID: 29171783 PMCID: PMC5806807 DOI: 10.1177/0394632017740061] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
It has been reported that hyperhomocysteinemia (HHcy) is associated with neurodegenerative and cardiovascular diseases. However, little is known about brain histomorphology, neuronal organelles, and hairy enhancer of split (hes) expression under HHcy. In this study, non-HHcy and HHcy induced by high-methionine diet in apolipoprotein E–deficient (Apo E−/−) mice were comparatively investigated. The histomorphology, ultrastructure, autophagosomes, apoptosis, and expression of proteins, HES1, HES5 and P62, were designed to assess the effects of HHcy on brain. The results showed that compared to the non-HHcy mice, the HHcy group had an increase in autophagosomes, vacuolization in mitochondria, and neuron apoptosis; treatment with folate and vitamin B12 reduced the extent of these lesions. However, the elementary histomorphology, the numbers of cortical neurons, and Nissl bodies had no significant difference between the HHcy and the non-HHcy groups or the group treated with folate and vitamin B12. Immunohistochemistry and immunofluorescence demonstrated a decrease in HES1- or HES5-positive neurons in the HHcy group when compared to the non-HHcy groups, wild-type, and Apo E−/− controls, or the HHcy mice with folate and vitamin B12 supplement. Western blots showed that HHcy induced a decreased expression of HES1 and HES5, or P62, in which the expression of HES1 and P62 was elevated by treating with folate and vitamin B12 supplement. These results suggest that HHcy-enhanced brain damage is associated with increased autophagy and neuronal apoptosis in Apo E−/− mice, in which downregulation of hes1 and hes5 is involved.
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Affiliation(s)
- Jing-Wen Zhang
- 1 Key Laboratory of Biomedical Information Engineering of Ministry of Education and Institute of Immunopathology, Medical School, Xi'an Jiaotong University, Xi'an, China.,2 School of Basic Medical Science, Ningxia Key Laboratory of Cerebrocranial Diseases-Incubation Base of National Key Laboratory, Ningxia Medical University, Yinchuan, China
| | - Ru Yan
- 2 School of Basic Medical Science, Ningxia Key Laboratory of Cerebrocranial Diseases-Incubation Base of National Key Laboratory, Ningxia Medical University, Yinchuan, China.,3 Heart Centre, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Yu-Sheng Tang
- 2 School of Basic Medical Science, Ningxia Key Laboratory of Cerebrocranial Diseases-Incubation Base of National Key Laboratory, Ningxia Medical University, Yinchuan, China
| | - Yong-Zhen Guo
- 2 School of Basic Medical Science, Ningxia Key Laboratory of Cerebrocranial Diseases-Incubation Base of National Key Laboratory, Ningxia Medical University, Yinchuan, China
| | - Yue Chang
- 2 School of Basic Medical Science, Ningxia Key Laboratory of Cerebrocranial Diseases-Incubation Base of National Key Laboratory, Ningxia Medical University, Yinchuan, China
| | - Li Jing
- 2 School of Basic Medical Science, Ningxia Key Laboratory of Cerebrocranial Diseases-Incubation Base of National Key Laboratory, Ningxia Medical University, Yinchuan, China
| | - Yi-Li Wang
- 1 Key Laboratory of Biomedical Information Engineering of Ministry of Education and Institute of Immunopathology, Medical School, Xi'an Jiaotong University, Xi'an, China
| | - Jian-Zhong Zhang
- 2 School of Basic Medical Science, Ningxia Key Laboratory of Cerebrocranial Diseases-Incubation Base of National Key Laboratory, Ningxia Medical University, Yinchuan, China.,4 Department of Pathology, Ningxia Medical University, Yinchuan, China
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27
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Zhang HP, Wang YH, Ma SC, Zhang H, Yang AN, Yang XL, Zhang MH, Sun JM, Hao YJ, Jiang YD. Homocysteine inhibits endothelial progenitor cells proliferation via DNMT1-mediated hypomethylation of Cyclin A. Exp Cell Res 2017; 362:217-226. [PMID: 29155363 DOI: 10.1016/j.yexcr.2017.11.021] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Revised: 11/13/2017] [Accepted: 11/15/2017] [Indexed: 01/08/2023]
Abstract
Endothelial progenitor cells (EPCs) contribute to neovasculogenesis and reendothelialization of damaged blood vessels to maintain the endothelium. Dysfunction of EPCs is implicated in the pathogenesis of vascular injury induced by homocysteine (Hcy). We aimed to investigate the role of Cyclin A in Hcy-induced EPCs dysfunction and explore its molecular mechanism. In this study, by treatment of EPCs with Hcy, we found that the expression of Cyclin A mRNA and protein were significantly downregulated in a dose-dependent manner. Knockdown of Cyclin A prominently reduced proliferation of EPCs, while over-expression of Cyclin A significantly promoted the cell proliferation, suggesting that Hcy inhibits EPCs proliferation through downregulation of Cyclin A expression. In addition, epigenetic study also demonstrated that Hcy induces DNA hypomethylation of the Cyclin A promoter in EPCs through downregulated expression of DNMT1. Moreover, we found that Hcy treatment of EPCs leads to increased SAM, SAH and MeCP2, while the ratio of SAM/SAH and MBD expression decrease. In summary, our results indicate that Hcy inhibits Cyclin A expression through hypomethylation of Cyclin A and thereby suppress EPCs proliferation. These findings demonstrate a novel mechanism of DNA methylation mediated by DNMT1 in prevention of Hcy associated cardiovascular disease.
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Affiliation(s)
- Hui-Ping Zhang
- Department of Prenatal Diagnosis Center, General Hospital of Ningxia Medical University, Yinchuan 750004, China
| | - Yan-Hua Wang
- Department of Pathophysiology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan 750004, China; Ningxia Key Laboratory of Vascular Injury and Repair Research, Yinchuan 750004, China
| | - Sheng-Chao Ma
- Department of Pathophysiology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan 750004, China; Ningxia Key Laboratory of Vascular Injury and Repair Research, Yinchuan 750004, China
| | - Hui Zhang
- Department of Pathophysiology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan 750004, China; Ningxia Key Laboratory of Vascular Injury and Repair Research, Yinchuan 750004, China
| | - An-Ning Yang
- Department of Pathophysiology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan 750004, China; Ningxia Key Laboratory of Vascular Injury and Repair Research, Yinchuan 750004, China
| | - Xiao-Ling Yang
- Department of Pathophysiology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan 750004, China; Ningxia Key Laboratory of Vascular Injury and Repair Research, Yinchuan 750004, China
| | - Ming-Hao Zhang
- Department of Pathophysiology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan 750004, China; Ningxia Key Laboratory of Vascular Injury and Repair Research, Yinchuan 750004, China
| | - Jian-Min Sun
- Department of Pathogen Biology and Immunology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan 750004, China; Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden
| | - Yin-Ju Hao
- Department of Pharmacology, Ningxia Medical University, Yinchuan 750004, China
| | - Yi-Deng Jiang
- Department of Pathophysiology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan 750004, China; Ningxia Key Laboratory of Vascular Injury and Repair Research, Yinchuan 750004, China.
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28
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Fu Y, Wang X, Kong W. Hyperhomocysteinaemia and vascular injury: advances in mechanisms and drug targets. Br J Pharmacol 2017; 175:1173-1189. [PMID: 28836260 DOI: 10.1111/bph.13988] [Citation(s) in RCA: 101] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Revised: 07/27/2017] [Accepted: 08/12/2017] [Indexed: 12/14/2022] Open
Abstract
Homocysteine is a sulphur-containing non-proteinogenic amino acid. Hyperhomocysteinaemia (HHcy), the pathogenic elevation of plasma homocysteine as a result of an imbalance of its metabolism, is an independent risk factor for various vascular diseases, such as atherosclerosis, hypertension, vascular calcification and aneurysm. Treatments aimed at lowering plasma homocysteine via dietary supplementation with folic acids and vitamin B are more effective in preventing vascular disease where the population has a normally low folate consumption than in areas with higher dietary folate. To date, the mechanisms of HHcy-induced vascular injury are not fully understood. HHcy increases oxidative stress and its downstream signalling pathways, resulting in vascular inflammation. HHcy also causes vascular injury via endoplasmic reticulum stress. Moreover, HHcy up-regulates pathogenic genes and down-regulates protective genes via DNA demethylation and methylation respectively. Homocysteinylation of proteins induced by homocysteine also contributes to vascular injury by modulating intracellular redox state and altering protein function. Furthermore, HHcy-induced vascular injury leads to neuronal damage and disease. Also, an HHcy-activated sympathetic system and HHcy-injured adipose tissue also cause vascular injury, thus demonstrating the interactions between the organs injured by HHcy. Here, we have summarized the recent developments in the mechanisms of HHcy-induced vascular injury, which are further considered as potential therapeutic targets in this condition. LINKED ARTICLES This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.
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Affiliation(s)
- Yi Fu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Health Science Center, Beijing, China.,Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
| | - Xian Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Health Science Center, Beijing, China.,Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
| | - Wei Kong
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Health Science Center, Beijing, China.,Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
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29
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Ma SC, Cao JC, Zhang HP, Jiao Y, Zhang H, He YY, Wang YH, Yang XL, Yang AN, Tian J, Zhang MH, Yang XM, Lu GJ, Jin SJ, Jia YX, Jiang YD. Aberrant promoter methylation of multiple genes in VSMC proliferation induced by Hcy. Mol Med Rep 2017; 16:7775-7783. [PMID: 28944836 DOI: 10.3892/mmr.2017.7521] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Accepted: 08/10/2017] [Indexed: 11/06/2022] Open
Abstract
Vascular smooth muscle cell (VSMC) proliferation is a primary pathological event in atherosclerosis (AS), and homocysteine (Hcy) is an independent risk factor for AS. However, the underlying mechanisms are still lagging. Studies have used the combination of methylation of promoters of multiple genes to diagnose tumors, thus the aim of the current study was to investigate the role of methylation status of several genes in VSMCs treated with Hcy. CpG islands were identified in the promoters of platelet‑derived growth factor (PDGF), p53, phosphatase and tensin homologue on chromosome 10 (PTEN) and mitofusin 2 (MFN2). Hypomethylation was observed to occur in the promoter region of PDGF, hypermethylation in p53, PTEN and MFN2, and hypomethylation in two global methylation indicators, aluminium (Alu) and long interspersed nucleotide element‑1 (Line‑1). This was accompanied by an increase in the expression of PDGF, and reductions of p53, PTEN and MFN2, both in mRNA and protein levels. An elevation of S‑adenosylmethionine (SAM) and a reduction of S‑adenosylhomocysteine (SAH) and the SAM/SAH ratio were also identified. In conclusion, Hcy impacted methylation the of AS‑associated genes and global methylation status that mediate the cell proliferation, which may be a character of VSMCs treated with Hcy. The data provided evidence for mechanisms of VSMCs proliferation in AS induced by Hcy and may provide a new perspective for AS induced by Hcy.
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Affiliation(s)
- Sheng-Chao Ma
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China
| | - Jian-Cheng Cao
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China
| | - Hui-Ping Zhang
- Department of Prenatal Diagnosis Center, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China
| | - Yun Jiao
- Department of Infectious Disease, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China
| | - Hui Zhang
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China
| | - Yang-Yang He
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China
| | - Yan-Hua Wang
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China
| | - Xiao-Ling Yang
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China
| | - An-Ning Yang
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China
| | - Jue Tian
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China
| | - Ming-Hao Zhang
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China
| | - Xiao-Ming Yang
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China
| | - Guan-Jun Lu
- Department of Urinary Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China
| | - Shao-Ju Jin
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China
| | - Yue-Xia Jia
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China
| | - Yi-Deng Jiang
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China
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30
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Duan H, Li Y, Yan L, Yang H, Wu J, Qian P, Li B, Wang S. MicroRNA-217 suppresses homocysteine-induced proliferation and migration of vascular smooth muscle cells via N-methyl-D-aspartic acid receptor inhibition. Clin Exp Pharmacol Physiol 2017; 43:967-75. [PMID: 27333430 DOI: 10.1111/1440-1681.12611] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Revised: 05/10/2016] [Accepted: 06/20/2016] [Indexed: 11/29/2022]
Abstract
Hyperhomocysteine has become a critical risk for atherosclerosis and can stimulate proliferation and migration of vascular smooth muscle cells (VSMCs). N-methyl-D-aspartic acid receptor (NMDAR) is a receptor of homocysteine and mediates the effects of homocysteine on VSMCs. Bioinformatics analysis has shown NMDAR is a potential target of microRNA-217 (miR-217), which exerts multiple functions in cancer tumorigenesis and carotid plaque progression. In this study, we sought to investigate the role of miR-217 in VSMCs phenotype transition under homocysteine exposure and elucidate its effect on atherosclerotic plaque formation. After treating with several doses of homocysteine (0-8 × 10(-4) mol/L) for 24 hours, the expression of miR-217 in HA-VSMCs and rat aortic VSMCs was not altered. Intriguingly, the expression of NMDAR mRNA and protein was reduced by homocysteine in a dose-dependent manner. Transfection of miR-217 mimic significantly inhibited the proliferation and migration of VSMCs with homocysteine treatment, while transfection of miR-217 inhibitor promoted VSMCs migration. Moreover, miR-217 mimic down-regulated while miR-217 inhibitor up-regulated NMDAR protein expression but not NMDAR mRNA expression. Through luciferase reporter assay, we showed that miR-217 could directly bind to the 3'-UTR of NMDAR. MiR-217 mimic transfection also released the inhibition of cAMP-response element-binding protein (CREB)-PGC-1α signalling induced by homocysteine. Additionally, restoration of PGC-1α expression via AdPGC-1α infection markedly suppressed VSMCs proliferation through the degradation of NADPH oxidase (NOX1) and reduction of reactive oxygen species (ROS). Collectively, our study identified the role of miR-217 in regulating VSMCs proliferation and migration, which might serve as a target for atherosclerosis therapy.
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Affiliation(s)
- Hongyan Duan
- Department of Cardiology, Henan Provincial People's Hospital, Zhengzhou, China
| | - Yongqiang Li
- Department of Cardiology, Henan Provincial People's Hospital, Zhengzhou, China
| | - Lijie Yan
- Department of Cardiology, Henan Provincial People's Hospital, Zhengzhou, China
| | - Haitao Yang
- Department of Cardiology, Henan Provincial People's Hospital, Zhengzhou, China
| | - Jintao Wu
- Department of Cardiology, Henan Provincial People's Hospital, Zhengzhou, China
| | - Peng Qian
- Department of Cardiology, Henan Provincial People's Hospital, Zhengzhou, China
| | - Bing Li
- Department of Cardiology, Henan Provincial People's Hospital, Zhengzhou, China
| | - Shanling Wang
- Department of Cardiology, Henan Provincial People's Hospital, Zhengzhou, China
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Singh K, Pal D, Sinha M, Ghatak S, Gnyawali SC, Khanna S, Roy S, Sen CK. Epigenetic Modification of MicroRNA-200b Contributes to Diabetic Vasculopathy. Mol Ther 2017; 25:2689-2704. [PMID: 29037594 DOI: 10.1016/j.ymthe.2017.09.009] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2017] [Revised: 09/01/2017] [Accepted: 09/07/2017] [Indexed: 12/26/2022] Open
Abstract
Hyperglycemia (HG) induces genome-wide cytosine demethylation. Our previous work recognized miR-200b as a critical angiomiR, which must be transiently downregulated to initiate wound angiogenesis. Under HG, miR-200b downregulation is not responsive to injury. Here, we demonstrate that HG may drive vasculopathy by epigenetic modification of a miR promoter. In human microvascular endothelial cells (HMECs), HG also lowered DNA methyltransferases (DNMT-1 and DNMT-3A) and compromised endothelial function as manifested by diminished endothelial nitric oxide (eNOS), lowered LDL uptake, impaired Matrigel tube formation, lower NO production, and compromised VE-cadherin expression. Bisulfite-sequencing documented HG-induced miR-200b promoter hypomethylation in HMECs and diabetic wound-site endothelial cells. In HMECs, HG compromised endothelial function. Methyl donor S-adenosyl-L-methionine (SAM) corrected miR-200b promoter hypomethylaton and rescued endothelial function. In vivo, wound-site administration of SAM to diabetic mice improved wound perfusion by limiting the pathogenic rise of miR-200b. Quantitative stable isotope labeling by amino acids in cell culture (SILAC) proteomics and ingenuity pathway analysis identified HG-induced proteins and principal clusters in HMECs sensitive to the genetic inhibition of miR-200b. This work presents the first evidence of the miR-200b promoter methylation as a critical determinant of diabetic wound angiogenesis.
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Affiliation(s)
- Kanhaiya Singh
- Department of Surgery, Davis Heart and Lung Research Institute, Center for Regenerative Medicine & Cell-Based Therapies, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA
| | - Durba Pal
- Department of Surgery, Davis Heart and Lung Research Institute, Center for Regenerative Medicine & Cell-Based Therapies, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA
| | - Mithun Sinha
- Department of Surgery, Davis Heart and Lung Research Institute, Center for Regenerative Medicine & Cell-Based Therapies, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA
| | - Subhadip Ghatak
- Department of Surgery, Davis Heart and Lung Research Institute, Center for Regenerative Medicine & Cell-Based Therapies, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA
| | - Surya C Gnyawali
- Department of Surgery, Davis Heart and Lung Research Institute, Center for Regenerative Medicine & Cell-Based Therapies, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA
| | - Savita Khanna
- Department of Surgery, Davis Heart and Lung Research Institute, Center for Regenerative Medicine & Cell-Based Therapies, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA
| | - Sashwati Roy
- Department of Surgery, Davis Heart and Lung Research Institute, Center for Regenerative Medicine & Cell-Based Therapies, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA
| | - Chandan K Sen
- Department of Surgery, Davis Heart and Lung Research Institute, Center for Regenerative Medicine & Cell-Based Therapies, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA.
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Zhang Q, Feng Y, Liu P, Yang J. MiR-143 inhibits cell proliferation and invasion by targeting DNMT3A in gastric cancer. Tumour Biol 2017; 39:1010428317711312. [PMID: 28718369 DOI: 10.1177/1010428317711312] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Increasing evidence has suggested that MircroRNAs (miRNAs) dysregulated in pathogenesis and tumorigenicity in human cancers including gastric cancer (GC). MiR-143 had been reported to function as tumor suppressor in GC progression, however, the underlying function of miR-143 in GC still need to be well known. In the study, we revealed that miR-143 was significantly down-regulated in GC cell lines. Upregulation of miR-143 inhibited cell proliferation, invasion, S phase cell proportion and cell cycle related protein levels of Cyclin D1, CDK4 and CDK6 in GC. Furthermore, luciferase reporter assays demonstrated that DNMT3A was a direct target of miR-143 and Upregulation of miR-143 inhibited the DNMT3A mRNA and protein expression levels in GC cells. Moreover, we demonstrated that DNMT3A knockdown rescued the promoting effect of miR-143 inhibitor on cell proliferation in GC. Thus, these results demonstrated that miR-143 targeted DNMT3A in GC cells and inhibit GC tumorigenesis and progression, which may provide a novel therapeutic target of GC.
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Affiliation(s)
- Quan Zhang
- 1 Department of Oncology, The First Affiliated Hospital, Nanjing Medical University, Nanjing, China.,2 Department of Radiation Oncology, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, China
| | - Yong Feng
- 1 Department of Oncology, The First Affiliated Hospital, Nanjing Medical University, Nanjing, China.,3 Department of Oncology, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, China
| | - Ping Liu
- 1 Department of Oncology, The First Affiliated Hospital, Nanjing Medical University, Nanjing, China
| | - Jing Yang
- 4 Department of Cardiology, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, China
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Hu XQ, Dasgupta C, Xiao D, Huang X, Yang S, Zhang L. MicroRNA-210 Targets Ten-Eleven Translocation Methylcytosine Dioxygenase 1 and Suppresses Pregnancy-Mediated Adaptation of Large Conductance Ca 2+-Activated K + Channel Expression and Function in Ovine Uterine Arteries. Hypertension 2017; 70:HYPERTENSIONAHA.117.09864. [PMID: 28739977 PMCID: PMC5783798 DOI: 10.1161/hypertensionaha.117.09864] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Revised: 06/19/2017] [Accepted: 06/26/2017] [Indexed: 12/31/2022]
Abstract
Gestational hypoxia inhibits large conductance Ca2+-activated K+ (BKCa) channel expression and function in uterine arterial adaptation to pregnancy. Given the findings that microRNA-210 (miR-210) is increased in hypoxia during gestation and preeclampsia, the present study sought to investigate the role of miR-210 in the regulation of BKCa channel adaptation in the uterine artery. Gestational hypoxia significantly increased uterine vascular resistance and blood pressure in pregnant sheep and upregulated miR-210 in uterine arteries. MiR-210 bound to ovine ten-eleven translocation methylcytosine dioxygenase 1 mRNA 3' untranslated region and decreased ten-eleven translocation methylcytosine dioxygenase 1 mRNA and protein abundance in uterine arteries of pregnant sheep, as well as abrogated steroid hormone-induced upregulation of ten-eleven translocation methylcytosine dioxygenase 1 expression in uterine arteries of nonpregnant animals. In accordance, miR-210 blocked pregnancy- and steroid hormone-induced upregulation of BKCa channel β1 subunit expression in uterine arteries. Functionally, miR-210 suppressed BKCa channel current density in uterine arterial myocytes of pregnant sheep and inhibited steroid hormone-induced increases in BKCa channel currents in uterine arteries of nonpregnant animals. Blockade of endogenous miR-210 inhibited hypoxia-induced suppression of BKCa channel activity. In addition, miR-210 decreased BKCa channel-mediated relaxations and increased pressure-dependent myogenic tone of uterine arteries. Together, the results demonstrate that miR-210 plays an important role in the downregulation of ten-eleven translocation methylcytosine dioxygenase 1 and repression of BKCa channel function in uterine arteries, revealing a novel mechanism of epigenetic regulation in the maladaptation of uterine hemodynamics in gestational hypoxia and preeclampsia.
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Affiliation(s)
- Xiang-Qun Hu
- From the Lawrence D. Longo, MD Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, CA (X.-Q.H., C.D., D.X., X.H., L.Z.); and Department of Chemistry and Biochemistry, California State University, San Bernardino (S.Y.)
| | - Chiranjib Dasgupta
- From the Lawrence D. Longo, MD Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, CA (X.-Q.H., C.D., D.X., X.H., L.Z.); and Department of Chemistry and Biochemistry, California State University, San Bernardino (S.Y.)
| | - Daliao Xiao
- From the Lawrence D. Longo, MD Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, CA (X.-Q.H., C.D., D.X., X.H., L.Z.); and Department of Chemistry and Biochemistry, California State University, San Bernardino (S.Y.)
| | - Xiaohui Huang
- From the Lawrence D. Longo, MD Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, CA (X.-Q.H., C.D., D.X., X.H., L.Z.); and Department of Chemistry and Biochemistry, California State University, San Bernardino (S.Y.)
| | - Shumei Yang
- From the Lawrence D. Longo, MD Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, CA (X.-Q.H., C.D., D.X., X.H., L.Z.); and Department of Chemistry and Biochemistry, California State University, San Bernardino (S.Y.)
| | - Lubo Zhang
- From the Lawrence D. Longo, MD Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, CA (X.-Q.H., C.D., D.X., X.H., L.Z.); and Department of Chemistry and Biochemistry, California State University, San Bernardino (S.Y.).
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Liu K, Xuekelati S, Zhang Y, Yin Y, Li Y, Chai R, Li X, Peng Y, Wu J, Guo X. Expression levels of atherosclerosis-associated miR-143 and miR-145 in the plasma of patients with hyperhomocysteinaemia. BMC Cardiovasc Disord 2017. [PMID: 28633641 PMCID: PMC5477732 DOI: 10.1186/s12872-017-0596-0] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Background An elevated level of homocysteine (Hcy) in the blood is designated hyperhomocysteinaemia (Hhcy) and is regarded as a strong risk factor for the development of atherosclerosis (ATH), although the association remains controversial. Considered to be essential gene expression regulators, micro-RNAs (miRNAs) modulate cardiovascular disease development and thus can be regarded as potential biomarkers and therapeutic targets in atherosclerosis. The aim of the current study is to investigate the expression levels of atherosclerosis-associated miR-143 and miR-145 in Hhcy patients and predict the progress of atherosclerosis in Hhcy patients. Methods A total of 100 participants were enrolled and included normal control subjects (NC = 20), hyperhomocysteinaemia alone subjects (Hhcy = 25), hyperhomocysteinaemia and carotid artery atherosclerosis combined subjects (Hhcy + ATH = 30) and patients with standalone carotid artery atherosclerosis (ATH = 25). Plasma Hcy, supplementary biochemical parameters and carotid artery ultrasonography (USG) were measured in all participants. MicroRNA expression levels in the peripheral blood were calculated by real-time reverse transcription-polymerase chain reaction (qRT-PCR). The correlations of miR-143 and miR-145 with Hcy, blood lipid parameters and carotid artery atherosclerotic plaques were evaluated using Pearson’s correlation coefficients. Receiver operating characteristic (ROC) curve analyses were performed to evaluate the capacities of miR-143 and miR-145 for the detection of Hhcy and atherosclerosis patients. Results MiR-143 and miR-145 exhibited trends towards significance with stepwise decreases from the NC to Hhcy groups and then to the Hhcy + ATH and ATH groups. Similar results were observed in the carotid artery plaque group (Hhcy + ATH and ATH grups) compared with the no-plaque group (NC and Hhcy groups). The miR-143 expression level exhibited significant negative correlations with Hcy, total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-c). The miR-145 expression level exhibited significant negative correlations with Hcy, TC, triglyceride (TG) and LDL-c. MiR-143 and miR-145 exhibited the greatest area under the curves (AUCs) (0.775 and 0.681, respectively) for the detection of every Hhcy patient, including those in the Hhcy and Hhcy + ATH groups, from among all subjects. Conclusion The results indicated that the levels of atherosclerosis-associated circulating miR-143 and miR-145 are linked to Hhcy. MiR-143 may be used as a potential non-invasive biomarkers of Hhcy and thus may be helpful in predicting the progress of atherosclerosis in Hhcy patients. Electronic supplementary material The online version of this article (doi:10.1186/s12872-017-0596-0) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Kejian Liu
- Department of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.,Department of Cardiology, the First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, China
| | - Saiyare Xuekelati
- The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University, Shihezi, Xinjiang, 832000, China
| | - Yue Zhang
- The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University, Shihezi, Xinjiang, 832000, China
| | - Yin Yin
- Department of Cardiology, the First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, China
| | - Yue Li
- Department of Cardiology, the First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, China
| | - Rui Chai
- Department of Cardiology, the First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, China
| | - Xinwei Li
- Department of Cardiology, the First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, China
| | - Yi Peng
- Department of Cardiology, the First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, China
| | - Jiangdong Wu
- The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University, Shihezi, Xinjiang, 832000, China.
| | - Xiaomei Guo
- Department of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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Li Z, Bai P, Peng D, Wang H, Guo Y, Jiang Y, He W, Tian H, Yang Y, Huang Y, Long B, Liang W, Zhang L. Screening and confirmation of microRNA markers for distinguishing between menstrual and peripheral blood. Forensic Sci Int Genet 2017; 30:24-33. [PMID: 28605652 DOI: 10.1016/j.fsigen.2017.05.012] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Revised: 05/19/2017] [Accepted: 05/30/2017] [Indexed: 12/31/2022]
Abstract
The identification of menstrual blood (MB) and peripheral blood (PB) left at a crime scene is crucial for crime reconstruction, especially in sexual assaults. MicroRNAs (miRNAs), a class of non-protein coding molecules, have been demonstrated to be a viable tool for body fluid identification in forensic casework. Several groups have searched for miRNAs that are specific to different body fluids. Blood has been studied the most extensively. However, menstrual blood was only involved in five studies, and the results confirming the presence of specific miRNAs could not be reproduced in other studies. In this study, we attempted to screen new markers that can differentiate between menstrual blood and peripheral blood by using Exiqon's miRCURY™ LNA Array. Five miRNAs were selected based on the microarray results, namely, miR-141-3p, miR-373-3p, miR-497-5p, miR-143-5p, and miR-136-5p, whose expression levels exhibited 27.95-, 17.96-, 16.74-, 10.14-, and 9.21-fold changes, respectively, compared to the level in peripheral blood. Two classic quantitative methods, TaqMan hydrolysis probes (TaqMan for short) and SYBR Green fluorochrome (SYBR Green for short), were applied in the confirmation step to study the impact of different quantitative methods on the results. Three miRNAs (miR-141-3p, miR-497-5p, and miR-143-5p) were confirmed by TaqMan and one (miR-141-3p) by SYBR Green. Furthermore, bioinformatic methods were applied to interpret the candidate miRNAs. Our results established a multi-step procedure for body fluid identification and showed that the choice of quantitative method is important when miRNAs are used to identify the origin of blood samples.
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Affiliation(s)
- Zhilong Li
- Department of Forensic Genetics, West China School of Basic Science and Forensic Medicine, Sichuan University, Chengdu 610041, Sichuan, China
| | - Peng Bai
- Department of Forensic Genetics, West China School of Basic Science and Forensic Medicine, Sichuan University, Chengdu 610041, Sichuan, China
| | - Duo Peng
- Department of Forensic Genetics, West China School of Basic Science and Forensic Medicine, Sichuan University, Chengdu 610041, Sichuan, China
| | - Hui Wang
- Institute of Forensic Science, Chengdu Public Security Bureau, Chengdu 610081, Sichuan, China
| | - Yadong Guo
- Department of Forensic Science, School of Basic Medical Sciences, Central South University, Changsha 410000, Hunan, China
| | - Youjing Jiang
- Department of Forensic Genetics, West China School of Basic Science and Forensic Medicine, Sichuan University, Chengdu 610041, Sichuan, China
| | - Wang He
- Department of Criminal Science and Technology, Sichuan Police College, Luzhou 646000, Sichuan, China
| | - Huan Tian
- Department of Forensic Genetics, West China School of Basic Science and Forensic Medicine, Sichuan University, Chengdu 610041, Sichuan, China
| | - Yu Yang
- Institute of Criminal Science and Technology, Shenzhen Public Security Bureau, Shenzhen518000, Shenzhen, China
| | - Yuan Huang
- Department of Biochemistry and Molecular Biology, West China School of Basic Science and Forensic Medicine, Sichuan University, Chengdu 610041, Sichuan, China
| | - Bing Long
- Department of Criminal Science and Technology, Sichuan Police College, Luzhou 646000, Sichuan, China
| | - Weibo Liang
- Department of Forensic Genetics, West China School of Basic Science and Forensic Medicine, Sichuan University, Chengdu 610041, Sichuan, China.
| | - Lin Zhang
- Department of Forensic Genetics, West China School of Basic Science and Forensic Medicine, Sichuan University, Chengdu 610041, Sichuan, China.
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Zeng G, Xun W, Wei K, Yang Y, Shen H. MicroRNA-27a-3p regulates epithelial to mesenchymal transition via targeting YAP1 in oral squamous cell carcinoma cells. Oncol Rep 2016; 36:1475-82. [DOI: 10.3892/or.2016.4916] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Accepted: 05/30/2016] [Indexed: 11/06/2022] Open
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