Department of Molecular, Cell and Cancer Biology
Amino Acids, Peptides, and Proteins | Biochemistry, Biophysics, and Structural Biology | Cardiovascular Diseases | Cardiovascular System | Physiology
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.
Macrophages, Heart, Gene expression, Myocardial infarction, Inflammation, Small interfering RNA, Luciferase, Transfection
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Copyright: © 2020 Mia et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
DOI of Published Version
Mia MM, Cibi DM, Abdul Ghani SAB, Song W, Tee N, Ghosh S, Mao J, Olson EN, Singh MK. YAP/TAZ deficiency reprograms macrophage phenotype and improves infarct healing and cardiac function after myocardial infarction. PLoS Biol. 2020 Dec 2;18(12):e3000941. doi: 10.1371/journal.pbio.3000941. PMID: 33264286; PMCID: PMC7735680. Link to article on publisher's site
Mia MM, Cibi DM, Abdul Ghani SA, Song W, Tee N, Ghosh S, Mao J, Olson EN, Singh MK. (2020). YAP/TAZ deficiency reprograms macrophage phenotype and improves infarct healing and cardiac function after myocardial infarction. Open Access Publications by UMass Chan Authors. https://doi.org/10.1371/journal.pbio.3000941. Retrieved from https://escholarship.umassmed.edu/oapubs/4516
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