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Role of microRNAs in malignant heart diseases (868.5)
Author(s) -
Yang Baofeng,
Shan Hongli,
Chu Wenfeng,
Pan Zhenwei,
Zhang Yong,
Lu Yanjie
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.868.5
Subject(s) - downregulation and upregulation , cardiac fibrosis , fibrosis , gene knockdown , microrna , myocardial fibrosis , cardiac function curve , transforming growth factor , cancer research , medicine , biology , heart failure , cell culture , gene , genetics
Deregulated myocardial fibrosis is a major cause of cardiac dysfunction. The focus of this investigation was to elucidate the importance of miRNAs in the control of pathophysiological processes following cardiac fibrosis. Gain of function and loss of function approaches in a specific miRNA transgenic mouse models were employed in the present study. First, we found that the level of the miRNA is aberrantly upregulated in the border zone of infarcted heart of wild type (WT) mouse following cardiac fibrosis by occlusion of the left coronary artery (LCA). Moreover, myocardial interstitial fibrosis has been dramatically developed in the genetic mouse model with cardiac‐specific overexpression of the miRNA. This phenomena in cardiac fibrosis followed by dilated cardiomyopathy and subsequent cardiac failure. In contrast, extent of fibrosis is significantly reduced by the genetic mouse model with cardiac‐specific knockdown of the miRNA by occlusion of LCA and elimination of the miRNA by its antisense oligoribonucleotides (AMO) in cultured cardiac fibroblasts significantly also results in reduction of secretion of collagen. In terms of its effect mechanisms, the miRNA directly targets at transforming growth factor‐beta receptor (TGFBR), which acts as an inhibitor of TGF‐β signals, subsequently promotes the formation of type I ‐ type II receptor complex and activities TGF‐β signaling pathway. Upregulation of TGF‐β signaling by the miRNA targeting TGFBR in turn induces secretion of collagen in fibroblast and downregulation of TGFBR is also abolished by the AMO in cultured cardiac fibroblasts. Our finding indicates that miRNA can function as a potent regulator of myocardial interstitial fibrosis and represents a potential therapeutic target for cardiac fibrosis in general.