MicroRNA-532 protects the heart in acute myocardial infarction, and represses prss23, a positive regulator of endothelial-to-mesenchymal transition

• Published in: Cardiovascular research Vol. 113; no. 13; pp. 1603 - 1614
• Main Authors: Bayoumi, Ahmed S, Teoh, Jian-Peng, Aonuma, Tatsuya, Yuan, Zhize, Ruan, Xiaofen, Tang, Yaoliang, Su, Huabo, Weintraub, Neal L, Kim, Il-Man
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.11.2017
• Subjects: Animals; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Down-Regulation; Endothelial Cells - enzymology; Endothelial Cells - pathology; Epithelial-Mesenchymal Transition; Fibroblasts - enzymology; Fibroblasts - pathology; Gene Knockdown Techniques; Mice, Inbred C57BL; MicroRNAs - genetics; MicroRNAs - metabolism; Myocardial Infarction - enzymology; Myocardial Infarction - genetics; Myocardial Infarction - pathology; Myocardial Infarction - prevention & control; Myocardium - enzymology; Myocardium - pathology; Neovascularization, Physiologic; Original; Phenotype; Serine Endopeptidases - genetics; Serine Endopeptidases - metabolism; Signal Transduction; Time Factors; β-Arrestin; Endothelial-to-mesenchymal transition; Cardioprotection; MicroRNAs; Biased G protein-coupled receptor signalling
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/cvx132

Acute myocardial infarction (MI) leads to cardiac remodelling and development of heart failure. Insufficient myocardial capillary density after MI is considered a critical determinant of this process. MicroRNAs (miRs), negative regulators of gene expression, have emerged as important players in MI. We previously showed that miR-532-5p (miR-532) is up-regulated by the β-arrestin-biased β-adrenergic receptor antagonist (β-blocker) carvedilol, which activates protective pathways in the heart independent of G protein-mediated second messenger signalling. Here, we hypothesize that β2-adrenergic receptor/β-arrestin-responsive miR-532 confers cardioprotection against MI. Using cultured cardiac endothelial cell (CEC) and in vivo approaches, we show that CECs lacking miR-532 exhibit increased transition to a fibroblast-like phenotype via endothelial-to-mesenchymal transition (EndMT), while CECs over-expressing miR-532 display decreased EndMT. We also demonstrate that knockdown of miR-532 in mice causes abnormalities in cardiac structure and function as well as reduces CEC proliferation and cardiac vascularization after MI. Mechanistically, cardioprotection elicited by miR-532 is in part attributed to direct repression of a positive regulator of maladaptive EndMT, prss23 (a protease serine 23) in CECs. In conclusion, these findings reveal a pivotal role for miR-532-prss23 axis in regulating CEC function after MI, and this novel axis could be suitable for therapeutic intervention in ischemic heart disease.