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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 5

Epicardial YAP and TAZ directly modulate the immune target IFN-γ in the acute recovery phase after MI.

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Epicardial YAP and TAZ directly modulate the immune target IFN-γ in the ...
(A and B) Bar graph and volcano plot of qRT-PCR immune arrays from microdissected LV free walls of control (Yapfl/fl Tazfl/fl) and mutant (Wt1CreERT2/+ Yapfl/fl Tazfl/fl) animals 3 days after MI. Green bars/circles represent statistically significant upregulated genes, and red bars/circles represent significantly downregulated genes in mutant mice versus control mice (n = 3 in both groups, P < 0.10). (B) Circles above the dotted line have a P value of less than 0.05. Data for each gene were compared using a 2-tailed Student’s t test. (C) Bar graph showing specific fold changes for up- and downregulated genes in the qRT-PCR immune arrays (n = 3 in both groups). (D and E) Luciferase reporter assays in HEK293T cells using various fragments of the IFNG promoter in the presence or absence of YAP, TAZ, or dnTEAD, as indicated. (F) YAP ChIP demonstrated significant YAP occupancy at the IFNG promoter (0 to –1 kb). n = 3 for all pairwise comparisons. Data in A–D represent the mean ± SD; data in F represent the mean ± SEM. #P < 0.10, *P < 0.05, **P< 0.01, and ***P < 0.001, by 2-tailed Student’s t test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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