YAP/TAZ deficiency reprograms macrophage phenotype and improves infarct healing and cardiac function after myocardial infarction

Abstract

Adverse cardiac remodeling after myocardial infarction (MI) causes structural and functional changes in the heart leading to heart failure. The initial post-MI pro-inflammatory response followed by reparative or anti-inflammatory response is essential for minimizing the myocardial damage, healing, and scar formation. Bone marrow–derived macrophages (BMDMs) are recruited to the injured myocardium and are essential for cardiac repair as they can adopt both pro-inflammatory or reparative phenotypes to modulate inflammatory and reparative responses, respectively. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are the key mediators of the Hippo signaling pathway and are essential for cardiac regeneration and repair. However, their functions in macrophage polarization and post-MI inflammation, remodeling, and healing are not well established. Here, we demonstrate that expression of YAP and TAZ is increased in macrophages undergoing pro-inflammatory or reparative phenotype changes. Genetic deletion of YAP/TAZ leads to impaired pro-inflammatory and enhanced reparative response. Consistently, YAP activation enhanced pro-inflammatory and impaired reparative response. We show that YAP/TAZ promote pro-inflammatory response by increasing interleukin 6 (IL6) expression and impede reparative response by decreasing Arginase-I (Arg1) expression through interaction with the histone deacetylase 3 (HDAC3)-nuclear receptor corepressor 1 (NCoR1) repressor complex. These changes in macrophages polarization due to YAP/TAZ deletion results in reduced fibrosis, hypertrophy, and increased angiogenesis, leading to improved cardiac function after MI. Also, YAP activation augmented MI-induced cardiac fibrosis and remodeling. In summary, we identify YAP/TAZ as important regulators of macrophage-mediated pro-inflammatory or reparative responses post-MI.

Critical role of the BAF chromatin remodeling complex during murine neural crest development

“…Expression of Hippo signaling pathway components such as Yap, Tead1, Tead2, Tead3, Amot, and Axin2 was significantly decreased in BAF155/170-deficient (Wnt1 Cre/ + ;BAF155 fl/fl ;BAF170 fl/fl ) NCCs. Hippo signaling pathway is a highly conserved pathway that regulates cellular proliferation, differentiation, and survival [55][56][57][58][59][60][61]. The downstream effector's Yap and Taz interact with transcription factors including Tead1-4 to promote migration, proliferation, and differentiation of NCCs in different biological systems.…”

The spatial form periosteal-bone complex promotes bone regeneration by coordinating macrophage polarization and osteogenic-angiogenic events

“…used 3D micropores and 2D micropatterns to limit the spread of macrophages, which inhibited the inflammatory gene expression profile by reducing actin polymerization [ 53 ]. Evidence further showed that YAP (a mediator of mechanotransduction) could reprogram macrophage phenotypes in many diseases [ [54] , [55] , [56] ]. The results in this study indicated that YAP activity might be related to stiffness, and inhibition of actin-mediated nuclear translocation of YAP had the potential for inflammatory suppression.…”

MicroRNA‑138‑5p drives the progression of heart failure via inhibiting sirtuin 1 signaling

“…The incidence and mortality of HF are high, and it endangers the health of patients with cardiovascular and cerebrovascular diseases ( 18 ). Myocardial infarction is the main cause of HF ( 19 ). It is well known that cardiomyocytes are not renewable.…”