YAP/TAZ deficiency reprograms macrophage phenotype and improves infarct healing and cardiac function after myocardial infarction
Authors
Mia, Masum M.Cibi, Dasan Mary
Abdul Ghani, Siti Aishah Binte
Song, Weihua
Tee, Nicole
Ghosh, Sujoy
Mao, Junhao
Olson, Eric N.
Singh, Manvendra K.
UMass Chan Affiliations
Department of Molecular, Cell and Cancer BiologyDocument Type
Journal ArticlePublication Date
2020-12-02Keywords
MacrophagesHeart
Gene expression
Myocardial infarction
Inflammation
Small interfering RNA
Luciferase
Transfection
Amino Acids, Peptides, and Proteins
Biochemistry, Biophysics, and Structural Biology
Cardiovascular Diseases
Cardiovascular System
Physiology
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Show full item recordAbstract
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.Source
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
DOI
10.1371/journal.pbio.3000941Permanent Link to this Item
http://hdl.handle.net/20.500.14038/41725PubMed ID
33264286Related Resources
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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.Distribution License
http://creativecommons.org/licenses/by/4.0/ae974a485f413a2113503eed53cd6c53
10.1371/journal.pbio.3000941
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Except where otherwise noted, this item's license is described as 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.