Blockade of Fibroblast YAP Attenuates Cardiac Fibrosis and Dysfunction Through MRTF-A Inhibition

Abstract

Fibrotic remodeling of the heart in response to injury contributes to heart failure, yet therapies to treat fibrosis remain elusive. Yes-associated protein (YAP) is activated in cardiac fibroblasts by myocardial infarction, and genetic inhibition of fibroblast YAP attenuates myocardial infarction-induced cardiac dysfunction and fibrosis. YAP promotes myofibroblast differentiation and associated extracellular matrix gene expression through engagement of TEA domain transcription factor 1 and subsequent de novo expression of myocardin-related transcription factor A. Thus, fibroblast YAP is a promising therapeutic target to prevent fibrotic remodeling and heart failure.

Keywords: AngII, angiotensin II; Hippo signaling; MCM, Mer-Cre-Mer; MI, myocardial infarction; MRTF-A, myocardin-related transcription factor A; Mkl1, megakaryoblastic leukemia 1; NRCF, neonatal rat cardiac fibroblast; PDGFR, platelet-derived growth factor receptor; PE, phenylephrine; SMA, smooth muscle actin; TEAD, TEA domain transcription factor; TGF, transforming growth factor; YAP; YAP, yes-associated protein; cardiac fibrosis; heart failure; mRNA, messenger ribonucleic acid; myocardial infarction.