PMID- 31104361 OWN - NLM STAT- MEDLINE DCOM- 20200806 LR - 20210109 IS - 1582-4934 (Electronic) IS - 1582-1838 (Print) IS - 1582-1838 (Linking) VI - 23 IP - 7 DP - 2019 Jul TI - Aberrant MFN2 transcription facilitates homocysteine-induced VSMCs proliferation via the increased binding of c-Myc to DNMT1 in atherosclerosis. PG - 4611-4626 LID - 10.1111/jcmm.14341 [doi] AB - It is well-established that homocysteine (Hcy) is an independent risk factor for atherosclerosis. Hcy can promote vascular smooth muscle cell (VSMC) proliferation, it plays a key role in neointimal formation and thus contribute to arteriosclerosis. However, the molecular mechanism on VSMCs proliferation underlying atherosclerosis is not well elucidated. Mitofusin-2 (MFN2) is an important transmembrane GTPase in the mitochondrial outer membrane and it can block cells in the G0/G1 stage of the cell cycle. To investigate the contribution of aberrant MFN2 transcription in Hcy-induced VSMCs proliferation and the underlying mechanisms. Cell cycle analysis revealed a decreased proportion of VSMCs in G0/G1 and an increased proportion in S phase in atherosclerotic plaque of APOE(-/-) mice with hyperhomocystinaemia (HHcy) as well as in VSMCs exposed to Hcy in vitro. The DNA methylation level of MFN2 promoter was obviously increased in VSMCs treated with Hcy, leading to suppressed promoter activity and low expression of MFN2. In addition, we found that the expression of c-Myc was increased in atherosclerotic plaque and VSMCs treated with Hcy. Further study showed that c-Myc indirectly regulates MFN2 expression is duo to the binding of c-Myc to DNMT1 promoter up-regulates DNMT1 expression leading to DNA hypermethylation of MFN2 promoter, thereby inhibits MFN2 expression in VSMCs treated with Hcy. In conclusion, our study demonstrated that Hcy-induced hypermethylation of MFN2 promoter inhibits the transcription of MFN2, leading to VSMCs proliferation in plaque formation, and the increased binding of c-Myc to DNMT1 promoter is a new and relevant molecular mechanism. CI - (c) 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine. FAU - Xu, Long AU - Xu L AD - Ningxia Vascular Injury and Repair Research Key Laboratory, Ningxia Medical University, Yinchuan, China. AD - School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, Ningxia, China. FAU - Hao, Hongyi AU - Hao H AD - The People's Hospital in Ningxia Hui Autonomous Region, Yinchuan, China. FAU - Hao, Yinju AU - Hao Y AD - The People's Hospital in Ningxia Hui Autonomous Region, Yinchuan, China. FAU - Wei, Guo AU - Wei G AD - Ningxia Vascular Injury and Repair Research Key Laboratory, Ningxia Medical University, Yinchuan, China. AD - School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, Ningxia, China. FAU - Li, Guizhong AU - Li G AD - Ningxia Vascular Injury and Repair Research Key Laboratory, Ningxia Medical University, Yinchuan, China. AD - School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, Ningxia, China. FAU - Ma, Pengjun AU - Ma P AD - Ningxia Vascular Injury and Repair Research Key Laboratory, Ningxia Medical University, Yinchuan, China. AD - Department of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia, China. FAU - Xu, Lingbo AU - Xu L AD - Ningxia Vascular Injury and Repair Research Key Laboratory, Ningxia Medical University, Yinchuan, China. AD - School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, Ningxia, China. FAU - Ding, Ning AU - Ding N AD - Ningxia Vascular Injury and Repair Research Key Laboratory, Ningxia Medical University, Yinchuan, China. AD - School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, Ningxia, China. FAU - Ma, Shengchao AU - Ma S AD - Ningxia Vascular Injury and Repair Research Key Laboratory, Ningxia Medical University, Yinchuan, China. AD - School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, Ningxia, China. FAU - Chen, Alex F AU - Chen AF AD - Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. FAU - Jiang, Yideng AU - Jiang Y AUID- ORCID: 0000-0001-6339-3970 AD - Ningxia Vascular Injury and Repair Research Key Laboratory, Ningxia Medical University, Yinchuan, China. AD - School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, Ningxia, China. LA - eng SI - GENBANK/NM_001127660.1 PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190518 PL - England TA - J Cell Mol Med JT - Journal of cellular and molecular medicine JID - 101083777 RN - 0 (Proto-Oncogene Proteins c-myc) RN - 0LVT1QZ0BA (Homocysteine) RN - EC 2.1.1.37 (DNA (Cytosine-5-)-Methyltransferase 1) RN - EC 3.6.1.- (GTP Phosphohydrolases) RN - EC 3.6.1.- (Mfn2 protein, mouse) SB - IM MH - Animals MH - Atherosclerosis/*genetics/pathology MH - Base Sequence MH - Cell Proliferation/drug effects MH - DNA (Cytosine-5-)-Methyltransferase 1/*metabolism MH - GTP Phosphohydrolases/*genetics/metabolism MH - Gene Expression Regulation/drug effects MH - Homocysteine/*pharmacology MH - Humans MH - Male MH - Mice, Inbred C57BL MH - Models, Biological MH - Muscle, Smooth, Vascular/*pathology MH - Myocytes, Smooth Muscle/drug effects/metabolism/*pathology MH - Plaque, Atherosclerotic/pathology MH - Promoter Regions, Genetic/genetics MH - Protein Binding/drug effects MH - Proto-Oncogene Proteins c-myc/*metabolism MH - *Transcription, Genetic/drug effects PMC - PMC6584594 OTO - NOTNLM OT - DNA methylation OT - c-Myc OT - homocysteine OT - mitofusin-2 OT - proliferation COIS- The authors declare that there are no conflicts of interest. EDAT- 2019/05/20 06:00 MHDA- 2020/08/07 06:00 PMCR- 2019/07/01 CRDT- 2019/05/20 06:00 PHST- 2018/12/01 00:00 [received] PHST- 2019/02/28 00:00 [revised] PHST- 2019/04/05 00:00 [accepted] PHST- 2019/05/20 06:00 [pubmed] PHST- 2020/08/07 06:00 [medline] PHST- 2019/05/20 06:00 [entrez] PHST- 2019/07/01 00:00 [pmc-release] AID - JCMM14341 [pii] AID - 10.1111/jcmm.14341 [doi] PST - ppublish SO - J Cell Mol Med. 2019 Jul;23(7):4611-4626. doi: 10.1111/jcmm.14341. Epub 2019 May 18.