Yes-associated Protein Isoform 1 (Yap1) Promotes Cardiomyocyte Survival and Growth to Protect against Myocardial Ischemic Injury*

Background: Yap1 regulates cardiac development, yet the function of Yap1 in the adult heart remains unknown. Results: Yap1 promotes cardiomyocyte survival, hypertrophy, and proliferation and protects against chronic myocardial infarction (MI). Conclusion: Yap1 is critical for basal heart homeostasis, and Yap1 deficiency exacerbates myocardial injury. Significance: Increasing cardiomyocyte survival and proliferation may afford protection in vivo against MI injury. Yap1 is an important regulator of cardiomyocyte proliferation and embryonic heart development, yet the function of endogenous Yap1 in the adult heart remains unknown. We studied the role of Yap1 in maintaining basal cardiac function and in modulating injury after chronic myocardial infarction (MI). Cardiomyocyte-specific homozygous inactivation of Yap1 in the postnatal heart (YapF/FCre) elicited increased myocyte apoptosis and fibrosis, dilated cardiomyopathy, and premature death. Heterozygous deletion (Yap+/FCre) did not cause an overt cardiac phenotype compared with YapF/F control mice at base line. In response to stress (MI), nuclear Yap1 was found selectively in the border zone and not in the remote area of the heart. After chronic MI (28 days), Yap+/FCre mice had significantly increased myocyte apoptosis and fibrosis, with attenuated compensatory cardiomyocyte hypertrophy, and further impaired function versus Yap+/F control mice. Studies in isolated cardiomyocytes demonstrated that Yap1 expression is sufficient to promote increased cell size and hypertrophic gene expression and protected cardiomyocytes against H2O2-induced cell death, whereas Yap1 depletion attenuated phenylephrine-induced hypertrophy and augmented apoptosis. Finally, we observed a significant decrease in cardiomyocyte proliferation in Yap+/FCre hearts compared with Yap+/F controls after MI and demonstrated that Yap1 is sufficient to promote cardiomyocyte proliferation in isolated cardiomyocytes. Our findings suggest that Yap1 is critical for basal heart homeostasis and that Yap1 deficiency exacerbates injury in response to chronic MI.

• Publication year

  2012

• Venue

  Journal of Biological Chemistry

• Publication date

  2012-12-30

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1074/jbc.M112.436311PMID 23275380PMCID PMC3567650
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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