title: Myocyte Enhancer Factor 2A Regulates Hydrogen Peroxide-Induced Senescence of Vascular Smooth Muscle Cells Via microRNA-143.
abstract: Myocyte enhancer factor 2A (MEF2A) is involved in vascular smooth muscle cell (VSMC) proliferation, migration, and senescence. MicroRNA-143/145 (miR-143/145), which may be regulated by MEF2A, is known to promote cellular senescence. We hypothesized that MEF2A may promote VSMC senescence via miR-143/145. VSMC senescence was induced by hydrogen peroxide (H(2)O(2)), followed by detection using a senescence-associated β-galactosidase staining kit. The MEF2A protein, mRNA, and miR-143/145 levels in VSMCs were detected using Western blot analysis and SYBR green real-time quantitative PCR, respectively. We further manipulated the expression levels of MEF2A and miR-143 through viral or transient transfection. VSMC proliferation and migration were determined by methylthiazolyldiphenyl-tetrazolium bromide and Millicell chamber, respectively. Both MEF2A and miR-143, but not miRNA-145, were up-regulated in senescent VSMCs. Overexpression of either MEF2A or miR-143 significantly enhanced VSMC senescence, but reduced proliferation and migration. MEF2A knockdown or miR-143 inhibitor suppressed cellular senescence and increased proliferation and migration. We further revealed AKT signaling as a potential miR-143 target, and an induction of miR-143 expression by MEF2A via KLF2. Additionally, overexpression of MEF2A and miR-143 resulted in synergistic effects on promotion of senescence, and MEF2A knockdown and miR-143 reduction by inhibitor had synergistic inhibitory effects. Finally, MEF2A barely promoted VSMC senescence when miR-143 was inhibited, and miR-143 overexpression antagonized the inhibitory effect of MEF2A knockdown on VSMC senescence. Our results revealed a link and interaction between MEF2A and miR-143 and suggested a potential mechanism for MEF2A to regulate H(2)O(2) -induced VSMC senescence.
authors: Department of Cardiology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors: Wang
authors: W
authors: Zhao
authors: Department of Biochemistry and Molecular Biology, The Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, The University of Calgary, Health Sciences Center, Calgary, Alberta, Canada.
authors: Xi-Long
authors: XL
authors: Zheng
authors: Department of Cardiology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors: Dao-Quan
authors: DQ
authors: Peng
authors: Department of Cardiology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors: Shui-Ping
authors: SP
authors: Zhao
mesh_terms: D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000008:administration & dosage; D064326:MEF2 Transcription Factors / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D064326:MEF2 Transcription Factors; C578035:MEF2A protein, human; C542359:MIRN143 microRNA, human; C541010:MIRN145 microRNA, human; D035683:MicroRNAs; D006861:Hydrogen Peroxide