title: DNMT3A silencing RASSF1A promotes cardiac fibrosis through upregulation of ERK1/2.
abstract: Cardiac fibrosis contributes to the pathogenesis of atrial fibrillation (AF). The molecular mechanisms underlying the cardiac fibrosis remain unclear. However, Ras association domain family 1 isoform A (RASSF1A) is a regulatory tumor suppressor, which is important for pathogenesis of cardiac fibrosis and fibroblasts activation. Moreover, DNA methylation plays a central role in the maintenance of cardiac fibrosis. DNA methyltransferases 3A (DNMT3A) is a critical participant in the epigenetic silencing of regulatory genes. Here, we report that the downregulation of RASSF1A in cardiac fibrosis is associated with DNMT3A. Treatment of cardiac fibroblasts with DNMT3A inhibitor 5-AzadC blocked proliferation. 5-AzadC also prevented the loss of RASSF1A expression that occurs during activated cardiac fibroblasts. To determine the underlying molecular mechanisms, we hypothesized that cardiac fibrosis is controlled by DNMT3A. We demonstrated that downregulation of RASSF1A is associated with cardiac fibrosis and fibroblasts activation. Knockdown of DNMT3A elevated RASSF1A expression in activated cardiac fibroblasts. Moreover, we investigated the effect of RASSF1A on the Ras/ERK pathway. Upregulation of p-ERK1/2 was detected in activated cardiac fibroblasts with decreased RASSF1A expression. Our results have shown that DNMT3A likely plays an essential role in RASSF1A mediated upregulation of ERK1/2 in rat cardiac fibrosis. DNMT3A and RASSF1A may serve as a new mechanism for cardiac fibrosis.
authors.affiliation: Department of Cardiothoracic Surgery, The Second Hospital of Anhui Medical University, Fu Rong Road, Hefei, Anhui 230601, China; Cardiovascular Research Center, Anhui Medical University, Hefei 230601, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Tao
authors.affiliation: Department of Pharmacology, The Second Hospital of Anhui Medical University, Hefei 230601, China. Electronic address: yjjncs01@126.com.
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Yang
authors.affiliation: Department of Cardiothoracic Surgery, The Second Hospital of Anhui Medical University, Fu Rong Road, Hefei, Anhui 230601, China; Cardiovascular Research Center, Anhui Medical University, Hefei 230601, China.
authors.forename: Ze-Wen
authors.initials: ZW
authors.lastname: Chen
authors.affiliation: Department of Cardiothoracic Surgery, The Second Hospital of Anhui Medical University, Fu Rong Road, Hefei, Anhui 230601, China; Cardiovascular Research Center, Anhui Medical University, Hefei 230601, China.
authors.forename: Sheng-Song
authors.initials: SS
authors.lastname: Xu
authors.affiliation: Department of Cardiothoracic Surgery, The Second Hospital of Anhui Medical University, Fu Rong Road, Hefei, Anhui 230601, China; Cardiovascular Research Center, Anhui Medical University, Hefei 230601, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Cardiothoracic Surgery, The Second Hospital of Anhui Medical University, Fu Rong Road, Hefei, Anhui 230601, China; Cardiovascular Research Center, Anhui Medical University, Hefei 230601, China.
authors.forename: Hong-Ying
authors.initials: HY
authors.lastname: Zhan
authors.affiliation: Department of Cardiothoracic Surgery, The Second Hospital of Anhui Medical University, Fu Rong Road, Hefei, Anhui 230601, China; Cardiovascular Research Center, Anhui Medical University, Hefei 230601, China. Electronic address: ayskh3@hotmail.com.
authors.forename: Kai-Hu
authors.initials: KH
authors.lastname: Shi
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics; D000090602:Collagen Type I, alpha 1 Chain; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D000090205:DNA Methyltransferase 3A; D000077209:Decitabine; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis; D020868:Gene Silencing; D007545:Isoproterenol; D020935:MAP Kinase Signaling System; D008297:Male; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D000199:Actins; D001374:Azacitidine; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D000077209:Decitabine; D007545:Isoproterenol; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; C560857:RASSF1 protein, rat; C498862:Acta2 protein, rat
keywords: Cardiac fibroblasts; Cardiac fibrosis; DNA methyltransferase 3A; Ras association domain family 1 isoform A; Smooth; muscle α-actin