Yes-associated protein (YAP) mediates adaptive cardiac hypertrophy in response to pressure overload

Jaemin Byun, Dominic P. Del Re, Peiyong Zhai, Shohei Ikeda, Akihiro Shirakabe, Wataru Mizushima, Shigeki Miyamoto, Joan H. Brown, Junichi Sadoshima

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)

Abstract

Cardiovascular disease (CVD) remains the leading cause of death globally, and heart failure is a major component of CVD-related morbidity and mortality. The development of cardiac hypertrophy in response to hemodynamic overload is initially considered to be beneficial; however, this adaptive response is limited and, in the presence of prolonged stress, will transition to heart failure. Yes-associated protein (YAP), the central downstream effector of the Hippo signaling pathway, regulates proliferation and survival in mammalian cells. Our previous work demonstrated that cardiac-specific loss of YAP leads to increased cardiomyocyte (CM) apoptosis and impaired CM hypertrophy during chronic myocardial infarction (MI) in the mouse heart. Because of its documented cardioprotective effects, we sought to determine the importance of YAP in response to acute pressure overload (PO). Our results indicate that endogenous YAP is activated in the heart during acute PO. YAP activation that depended upon RhoA was also observed in CMs subjected to cyclic stretch. To examine the function of endogenous YAP during acute PO, Yap/flox;Cre-MHC (YAP-CHKO) and Yap/flox mice were subjected to transverse aortic constriction (TAC). We found that YAP-CHKO mice had attenuated cardiac hypertrophy and significant increases in CM apoptosis and fibrosis that correlated with worsened cardiac function after 1 week of TAC. Loss of CM YAP also impaired activation of the cardioprotective kinase Akt, which may underlie the YAP-CHKO phenotype. Together, these data indicate a prohypertrophic, prosurvival function of endogenous YAP and suggest a critical role for CM YAP in the adaptive response to acute PO.

Original languageEnglish
Pages (from-to)3603-3617
Number of pages15
JournalJournal of Biological Chemistry
Volume294
Issue number10
DOIs
Publication statusPublished - 2019 Mar 8

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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