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Epicardial YAP/TAZ orchestrate an immunosuppressive response following myocardial infarction
Vimal Ramjee, … , Rajan Jain, Jonathan A. Epstein
Vimal Ramjee, … , Rajan Jain, Jonathan A. Epstein
Published February 6, 2017
Citation Information: J Clin Invest. 2017;127(3):899-911. https://doi.org/10.1172/JCI88759.
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Research Article Cardiology Cell biology

Epicardial YAP/TAZ orchestrate an immunosuppressive response following myocardial infarction

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Abstract

Ischemic heart disease resulting from myocardial infarction (MI) is the most prevalent form of heart disease in the United States. Post-MI cardiac remodeling is a multifaceted process that includes activation of fibroblasts and a complex immune response. T-regulatory cells (Tregs), a subset of CD4+ T cells, have been shown to suppress the innate and adaptive immune response and limit deleterious remodeling following myocardial injury. However, the mechanisms by which injured myocardium recruits suppressive immune cells remain largely unknown. Here, we have shown a role for Hippo signaling in the epicardium in suppressing the post-infarct inflammatory response through recruitment of Tregs. Mice deficient in epicardial YAP and TAZ, two core Hippo pathway effectors, developed profound post-MI pericardial inflammation and myocardial fibrosis, resulting in cardiomyopathy and death. Mutant mice exhibited fewer suppressive Tregs in the injured myocardium and decreased expression of the gene encoding IFN-γ, a known Treg inducer. Furthermore, controlled local delivery of IFN-γ following MI rescued Treg infiltration into the injured myocardium of YAP/TAZ mutants and decreased fibrosis. Collectively, these results suggest that epicardial Hippo signaling plays a key role in adaptive immune regulation during the post-MI recovery phase.

Authors

Vimal Ramjee, Deqiang Li, Lauren J. Manderfield, Feiyan Liu, Kurt A. Engleka, Haig Aghajanian, Christopher B. Rodell, Wen Lu, Vivienne Ho, Tao Wang, Li Li, Anamika Singh, Dasan M. Cibi, Jason A. Burdick, Manvendra K. Singh, Rajan Jain, Jonathan A. Epstein

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Figure 2

Deletion of epicardial YAP/TAZ results in profound pericardial inflammation and erosion of the heart through the chest wall.

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Deletion of epicardial YAP/TAZ results in profound pericardial inflammat...
(A) Whole-mount bright-field images of representative Yapfl/fl Tazfl/fl (control) and Wt1CreERT2/+ Yapfl/fl Tazfl/fl (mutant) hearts in the absence of surgery or following MI injury. Arrowheads indicate focal fibrosis at the site of the coronary ligature in control mice and a thick, fibrous cap covering the distal anterior LV wall and the entire cardiac apex in mutant mice. Scale bars: 2 mm. (B) Whole-mount bright-field images of representative Yapfl/fl Tazfl/fl (control) and Wt1CreERT2/+ Yapfl/fl Tazfl/fl (mutant) chest walls following MI injury. Arrowheads denote erosion of the cardiac apex and anterior LV wall through the soft tissue and bone structures of the anterior chest wall in mutant mice.
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