Yes-associated protein isoform 1 (Yapl) promotes cardiomyocyte survival and growth to protect against myocardial ischemic injury

Dominic P. Del Re, Yanfei Yang, Noritsugu Nakano, Jaeyeaon Cho, Peiyong Zhai, Takanobu Yamamoto, Nailing Zhang, Norikazu Yabuta, Hiroshi Nojima, Duojia Pan, Junichi Sadoshima

Research output: Contribution to journalArticle

111 Scopus citations

Abstract

Yapl is an important regulator of cardiomyocyte proliferation and embryonic heart development, yet the function of endogenous Yapl in the adult heart remains unknown. We studied the role of Yapl in maintaining basal cardiac function and in modulating injury after chronic myocardial infarction (MI). Cardiomyocyte-specific homozygous inactivation of Yapl in the postnatal heart (YapF/FCre) elicited increased myocyte apopto-sis and fibrosis, dilated cardiomyopathy, and premature death. Heterozygous deletion (Yap +/FCre) did not cause an overt cardiac phenotype compared with YapFIF control mice at base line. In response to stress (MI), nuclear Yapl 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 car-diomyocytes demonstrated that Yapl expression is sufficient to promote increased cell size and hypertrophic gene expression and protected cardiomyocytes against H 2O2-induced cell death, whereas Yapl depletion attenuated phenylephrine-induced hypertrophy and augmented apoptosis. Finally, we observed a significant decrease in cardiomyocyte proliferation in Yap+/F-Cre hearts compared with Yap+/F controls after MI and demonstrated that Yapl is sufficient to promote cardiomyocyte proliferation in isolated cardiomyocytes. Our findings suggest that Yapl is critical for basal heart homeostasis and that Yapl deficiency exacerbates injury in response to chronic MI.

Original languageEnglish (US)
Pages (from-to)3977-3988
Number of pages12
JournalJournal of Biological Chemistry
Volume288
Issue number6
DOIs
StatePublished - Feb 8 2013

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Del Re, D. P., Yang, Y., Nakano, N., Cho, J., Zhai, P., Yamamoto, T., Zhang, N., Yabuta, N., Nojima, H., Pan, D., & Sadoshima, J. (2013). Yes-associated protein isoform 1 (Yapl) promotes cardiomyocyte survival and growth to protect against myocardial ischemic injury. Journal of Biological Chemistry, 288(6), 3977-3988. https://doi.org/10.1074/jbc.M112.436311