PMID- 30529267 OWN - NLM STAT- MEDLINE DCOM- 20200108 LR - 20200108 IS - 1095-8584 (Electronic) IS - 0022-2828 (Linking) VI - 127 DP - 2019 Feb TI - Inhibition of BRD4 attenuates transverse aortic constriction- and TGF-beta-induced endothelial-mesenchymal transition and cardiac fibrosis. PG - 83-96 LID - S0022-2828(18)30782-X [pii] LID - 10.1016/j.yjmcc.2018.12.002 [doi] AB - Cardiac fibrosis (CF), a process characterized by potentiated proliferation of cardiac fibroblasts and excessive secretion and deposition of extracellular matrix (ECM) from the cells, contributes strongly to the pathogenesis of a series of cardiovascular (CV) diseases, including AMI, heart failure and atrial fibrillation. Endothelial-mesenchymal transition (EndMT), one of the sources of transformed cardiac fibroblasts, has been reported as a key factor involved in CF. However, the molecular basis of EndMT has not been thoroughly elucidated to date. At the posttranscriptional level, of the three epigenetic regulators, writer and eraser are reported to be involved in EndMT, but the role of reader in the process is still unknown. In this study, we aimed to explore the role of Bromodomain-containing protein 4 (BRD4), an acetyl-lysine reader protein, in EndMT-induced CF and related mechanisms. We found that BRD4 was upregulated in endothelial cells (ECs) in the pressure-overload mouse heart and that its functional inhibitor JQ1 potently attenuated the TAC-induced CF and preserved cardiac function. In umbilical vein endothelial cells (HUVECs) and mouse aortic endothelial cells (MAECs), bothJQ1 and shRNA-mediated silencing of BRD4 blocked TGF-beta-induced EC migration, EndMT and ECM synthesis and preserved the EC sprouting behavior, possibly through the downregulation of a group of transcription factors specific for EndMT (Snail, Twist and Slug), the Smads pathway and TGF-beta receptor I. In the absence of TGF-beta stimulation, ectopic expression of BRD4 alone could facilitate EndMT, accelerate migration and increase the synthesis of ECM. In vivo, JQ1 also attenuated TAC-induced EndMT and CF, which was consistent with JQ1's intracellular mechanisms of action. Our results showed that BRD4 plays a critical role in EndMT-induced CF and that targeting BRD4 might be a novel therapeutic option for CF. CI - Copyright (c) 2018. Published by Elsevier Ltd. FAU - Song, Shuai AU - Song S AD - Department of Cardiology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. FAU - Liu, Liang AU - Liu L AD - Department of Cardiology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, 200233, China. FAU - Yu, Yi AU - Yu Y AD - Department of Ultrasound, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. FAU - Zhang, Rui AU - Zhang R AD - Department of Cardiology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. FAU - Li, Yigang AU - Li Y AD - Department of Cardiology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. FAU - Cao, Wei AU - Cao W AD - Department of Cardiology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. FAU - Xiao, Ying AU - Xiao Y AD - Department of Cardiology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. FAU - Fang, Guojian AU - Fang G AD - Department of Cardiology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. FAU - Li, Zhen AU - Li Z AD - Department of Geriatrics, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. FAU - Wang, Xuelian AU - Wang X AD - Department of Geriatrics, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. FAU - Wang, Qi AU - Wang Q AD - Department of Cardiovascular Surgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China. FAU - Zhao, Xin AU - Zhao X AD - Department of Cardiovascular Surgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China. FAU - Chen, Long AU - Chen L AD - Department of Cardiovascular Surgery, Huadong Hospital Affiliated of Fudan University, 221 Yananxi Road, Shanghai 200040, China. FAU - Wang, Yuepeng AU - Wang Y AD - Department of Cardiology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. Electronic address: wangyuepeng@xinhuamed.com.cn. FAU - Wang, Qunshan AU - Wang Q AD - Department of Cardiology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. Electronic address: wangqunshan@xinhuamed.com.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20181207 PL - England TA - J Mol Cell Cardiol JT - Journal of molecular and cellular cardiology JID - 0262322 RN - 0 (BRD4 protein, human) RN - 0 (Biomarkers) RN - 0 (Brd4 protein, mouse) RN - 0 (Cell Cycle Proteins) RN - 0 (Extracellular Matrix Proteins) RN - 0 (Nuclear Proteins) RN - 0 (Receptors, Transforming Growth Factor beta) RN - 0 (Smad Proteins) RN - 0 (Transcription Factors) RN - 0 (Transforming Growth Factor beta) SB - IM MH - Animals MH - Aorta/*pathology MH - Biomarkers/metabolism MH - Cell Cycle Proteins/*metabolism MH - Cell Movement/drug effects MH - Constriction MH - Down-Regulation/drug effects MH - Extracellular Matrix Proteins/biosynthesis MH - Fibroblasts/metabolism MH - Fibrosis MH - Human Umbilical Vein Endothelial Cells/drug effects/*metabolism MH - Humans MH - Male MH - Mesoderm/*metabolism MH - Mice, Inbred C57BL MH - Myocardium/*pathology MH - Neovascularization, Physiologic/drug effects MH - Nuclear Proteins/*metabolism MH - Receptors, Transforming Growth Factor beta/metabolism MH - Signal Transduction MH - Smad Proteins/metabolism MH - Transcription Factors/*metabolism MH - Transforming Growth Factor beta/*adverse effects OTO - NOTNLM OT - BRD4 OT - Cardiac fibrosis OT - EndMT OT - Smads EDAT- 2018/12/12 06:00 MHDA- 2020/01/09 06:00 CRDT- 2018/12/12 06:00 PHST- 2018/08/09 00:00 [received] PHST- 2018/11/17 00:00 [revised] PHST- 2018/12/04 00:00 [accepted] PHST- 2018/12/12 06:00 [pubmed] PHST- 2020/01/09 06:00 [medline] PHST- 2018/12/12 06:00 [entrez] AID - S0022-2828(18)30782-X [pii] AID - 10.1016/j.yjmcc.2018.12.002 [doi] PST - ppublish SO - J Mol Cell Cardiol. 2019 Feb;127:83-96. doi: 10.1016/j.yjmcc.2018.12.002. Epub 2018 Dec 7.