Cardiomyocyte YAP represses myocardial inflammation and fibrosis and restrains MEF2-regulated gene expression

Cardiomyocyte signaling through the transcriptional coactivator Yes-associated protein (YAP) has been shown to protect the myocardium against ischemic or mechanical stress. Inflammatory responses initiated in cardiomyocytes play a major role in the development of cardiac dysfunction. We tested the relationship between YAP and inflammatory gene expression using cardiomyocyte-specific YAP-knockout (KO) mice. Wild-type (WT) and KO mice were infused with angiotensin II (AngII) at 1.5 μg/kg/min and euthanized 24 h or 3 days postinfusion. YAP deletion markedly enhanced AngII-induced mRNA expression of proinflammatory cytokines and chemokines, a response that occurred selectively within cardiomyocytes. Hearts from YAP-KO mice also had increased F4/80, CD68, and Col1 staining. Single-nuclei RNA sequencing of WT and YAP-KO hearts showed significant upregulation of proinflammatory cytokines and of a range of genes, including those in the Jun family, Camk2d, and Tlr4. Isolated cardiomyocytes transfected with YAP siRNA or a constitutively active YAP mutant showed, respectively, enhanced and decreased Jun, Camk2d and Tlr4 mRNA gene expression. HOMER motif enrichment analysis of differentially expressed genes from the snRNA-seq data revealed that the most highly upregulated transcripts in YAP-KO versus WT hearts were enriched in myocyte enhancer factor 2 (MEF2)-binding sites. Western blot analysis of hearts from YAP-KO mice treated with AngII showed increased MEF2C protein compared with WT hearts. MEF2C siRNA transfection diminished the potentiation of gene expression by siYAP in isolated cardiomyocytes, implicating MEF2 as a downstream YAP target. Our findings indicate that activation of cardiomyocyte YAP serves, in part, to repress MEF2-regulated genes and restrain cardiomyocyte inflammation.NEW & NOTEWORTHY YAP is increasingly recognized for its role in safeguarding the heart by regulating cardiac responses to mechanical and ischemic stress. Here, we highlight YAP's protective role in cardiomyocytes by restraining maladaptive inflammation and fibrosis in response to AngII stress. By selective deletion of cardiomyocyte YAP and single-nuclei RNA sequencing, we determine that YAP serves an anti-inflammatory role and suggest that this occurs through repression of MEF2-dependent pathways, advancing our understanding of how YAP functions in cardiac health and disease.