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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 March 1, 2017; First published February 6, 2017
Citation Information: J Clin Invest. 2017;127(3):899-911. https://doi.org/10.1172/JCI88759.
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Categories: 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 1

The epicardium is activated after myocardial infarction.

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The epicardium is activated after myocardial infarction.
(A) Experimenta...
(A) Experimental design. (B) Post-MI cross sections of Yapfl/fl Tazfl/fl (control) and Wt1CreERT2/+ Yapfl/fl Tazfl/fl (mutant) mice stained for Hoechst, YAP, TAZ, or merged (Hoechst/YAP or Hoechst/TAZ). Arrowheads denote YAP+ or TAZ+ cells. p-YAP, phosphorylated YAP. (C and D) Cross sections of Wt1CreERT2/+ Yapfl/fl Tazfl/fl R26Tomato/+ stained for Hoechst, Tomato, or merged (Hoechst/Tomato) 3 (C) or 14 (D) days after sham surgery or MI. Arrowheads denote Tomato+ cells in the epicardium. Scale bars: 25 μm (B and C) and 50 μm (D).
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