PMID- 24945829
OWN - NLM
STAT- MEDLINE
DCOM- 20140926
LR  - 20220321
IS  - 1879-3185 (Electronic)
IS  - 0300-483X (Linking)
VI  - 323
DP  - 2014 Sep 2
TI  - DNMT3A silencing RASSF1A promotes cardiac fibrosis through upregulation of 
      ERK1/2.
PG  - 42-50
LID - S0300-483X(14)00119-X [pii]
LID - 10.1016/j.tox.2014.06.006 [doi]
AB  - 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.
CI  - Copyright (c) 2014 Elsevier Ireland Ltd. All rights reserved.
FAU - Tao, Hui
AU  - Tao H
AD  - 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.
FAU - Yang, Jing-Jing
AU  - Yang JJ
AD  - Department of Pharmacology, The Second Hospital of Anhui Medical University, 
      Hefei 230601, China. Electronic address: yjjncs01@126.com.
FAU - Chen, Ze-Wen
AU  - Chen ZW
AD  - 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.
FAU - Xu, Sheng-Song
AU  - Xu SS
AD  - 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.
FAU - Zhou, Xiao
AU  - Zhou X
AD  - 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.
FAU - Zhan, Hong-Ying
AU  - Zhan HY
AD  - 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.
FAU - Shi, Kai-Hu
AU  - Shi KH
AD  - 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.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140616
PL  - Ireland
TA  - Toxicology
JT  - Toxicology
JID - 0361055
RN  - 0 (Actins)
RN  - 0 (Collagen Type I)
RN  - 0 (Collagen Type I, alpha 1 Chain)
RN  - 0 (RASSF1 protein, rat)
RN  - 0 (RNA, Messenger)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 0 (smooth muscle actin, rat)
RN  - 776B62CQ27 (Decitabine)
RN  - EC 2.1.1.37 (DNA (Cytosine-5-)-Methyltransferases)
RN  - EC 2.1.1.37 (DNA Methyltransferase 3A)
RN  - L628TT009W (Isoproterenol)
RN  - M801H13NRU (Azacitidine)
SB  - IM
MH  - Actins/metabolism
MH  - Animals
MH  - Animals, Newborn
MH  - Azacitidine/analogs & derivatives/pharmacology
MH  - Cells, Cultured
MH  - Collagen Type I/genetics
MH  - Collagen Type I, alpha 1 Chain
MH  - DNA (Cytosine-5-)-Methyltransferases/*metabolism
MH  - DNA Methyltransferase 3A
MH  - Decitabine
MH  - Fibroblasts/drug effects/metabolism
MH  - Fibrosis
MH  - Gene Silencing
MH  - Isoproterenol
MH  - MAP Kinase Signaling System
MH  - Male
MH  - Myocardium/*metabolism/*pathology
MH  - RNA, Messenger/metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Tumor Suppressor Proteins/*genetics/metabolism
OTO - NOTNLM
OT  - Cardiac fibroblasts
OT  - Cardiac fibrosis
OT  - DNA methyltransferase 3A
OT  - Ras association domain family 1 isoform A
OT  - Smooth
OT  - muscle alpha-actin
EDAT- 2014/06/20 06:00
MHDA- 2014/09/27 06:00
CRDT- 2014/06/20 06:00
PHST- 2014/04/28 00:00 [received]
PHST- 2014/06/12 00:00 [revised]
PHST- 2014/06/13 00:00 [accepted]
PHST- 2014/06/20 06:00 [entrez]
PHST- 2014/06/20 06:00 [pubmed]
PHST- 2014/09/27 06:00 [medline]
AID - S0300-483X(14)00119-X [pii]
AID - 10.1016/j.tox.2014.06.006 [doi]
PST - ppublish
SO  - Toxicology. 2014 Sep 2;323:42-50. doi: 10.1016/j.tox.2014.06.006. Epub 2014 Jun 
      16.