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

• Published in: PLoS biology Vol. 18; no. 12; p. e3000941
• Main 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
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 02.12.2020; Public Library of Science (PLoS)
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Adaptor Proteins, Signal Transducing - physiology; Angiogenesis; Animals; Arginase; Biological Variation, Population - genetics; Biological Variation, Population - physiology; Biology and Life Sciences; Bone marrow; Cell Cycle Proteins - metabolism; Cell Cycle Proteins - physiology; Collagen; Complications and side effects; Congestive heart failure; Cytokines; Egr-2 protein; Female; Fibroblast growth factor 2; Gene expression; Genetic aspects; Genetic transcription; Genotype & phenotype; Glyceraldehyde-3-phosphate dehydrogenase; Growth factors; Health aspects; Heart; Heart attack; Heart attacks; Heart failure; Identification and classification; Inflammation; Inflammation - metabolism; Interferon; Interleukin 10; Interleukin 6; Lipopolysaccharides; Macrophages; Macrophages - metabolism; Macrophages - physiology; Male; Medicine and Health Sciences; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Transgenic; Myocardial infarction; Myocardial Infarction - metabolism; Myocardial Infarction - pathology; Myocardium - metabolism; Nitric oxide; Nitric-oxide synthase; Peritoneum; Phenotype; Phenotypes; Phosphoproteins - metabolism; Physiological aspects; Protein expression; Proteins; Research and Analysis Methods; Reverse transcription; Signal Transduction; siRNA; Structural integrity; Therapeutic targets; Trans-Activators - metabolism; Trans-Activators - physiology; Transcription Factors - metabolism; Vascular endothelial growth factor; Vascularization; Ventricle; Yes-associated protein; γ-Interferon; Singapore
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.3000941

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.