Hippo pathway effector Yap promotes cardiac regeneration

Mei Xin, Yuri Kim, Lillian B. Sutherland, Masao Murakami, Xiaoxia Qi, John McAnally, Enzo R. Porrello, Ahmed I. Mahmoud, Wei Tan, John M. Shelton, James A. Richardson, Hesham A. Sadek, Rhonda Bassel-Duby, Eric N. Olson

Research output: Contribution to journalArticle

407 Scopus citations

Abstract

The adult mammalian heart has limited potential for regeneration. Thus, after injury, cardiomyocytes are permanently lost, and contractility is diminished. In contrast, the neonatal heart can regenerate owing to sustained cardiomyocyte proliferation. Identification of critical regulators of cardiomyocyte proliferation and quiescence represents an important step toward potential regenerative therapies. Yes-associated protein (Yap), a transcriptional cofactor in the Hippo signaling pathway, promotes proliferation of embryonic cardiomyocytes by activating the insulin-like growth factor and Wnt signaling pathways. Here we report that mice bearing mutant alleles of Yap and its paralog WW domain containing transcription regulator 1 (Taz) exhibit gene dosage-dependent cardiac phenotypes, suggesting redundant roles of these Hippo pathway effectors in establishing proper myocyte number and maintaining cardiac function. Cardiac-specific deletion of Yap impedes neonatal heart regeneration, resulting in a default fibrotic response. Conversely, forced expression of a constitutively active form of Yap in the adult heart stimulates cardiac regeneration and improves contractility after myocardial infarction. The regenerative activity of Yap is correlated with its activation of embryonic and proliferative gene programs in cardiomyocytes. These findings identify Yap as an important regulator of cardiac regeneration and provide an experimental entry point to enhance this process.

Original languageEnglish (US)
Pages (from-to)13839-13844
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number34
DOIs
StatePublished - 2013

Keywords

  • Cardiac fibrosis
  • Cardiomyopathy
  • Cell cycle

ASJC Scopus subject areas

  • General

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    Xin, M., Kim, Y., Sutherland, L. B., Murakami, M., Qi, X., McAnally, J., Porrello, E. R., Mahmoud, A. I., Tan, W., Shelton, J. M., Richardson, J. A., Sadek, H. A., Bassel-Duby, R., & Olson, E. N. (2013). Hippo pathway effector Yap promotes cardiac regeneration. Proceedings of the National Academy of Sciences of the United States of America, 110(34), 13839-13844. https://doi.org/10.1073/pnas.1313192110