title: Yes-associated protein isoform 1 (Yap1) promotes cardiomyocyte survival and growth to protect against myocardial ischemic injury.
abstract: 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 (Yap(F/F)Cre) elicited increased myocyte apoptosis and fibrosis, dilated cardiomyopathy, and premature death. Heterozygous deletion (Yap(+/F)Cre) did not cause an overt cardiac phenotype compared with Yap(F/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(+/F)Cre 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 H(2)O(2)-induced cell death, whereas Yap1 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 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.
authors.affiliation: Cardiovascular Research Institute and Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey 07103, USA.
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Del Re
authors.forename: Yanfei
authors.initials: Y
authors.lastname: Yang
authors.forename: Noritsugu
authors.initials: N
authors.lastname: Nakano
authors.forename: Jaeyeaon
authors.initials: J
authors.lastname: Cho
authors.forename: Peiyong
authors.initials: P
authors.lastname: Zhai
authors.forename: Takanobu
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Nailing
authors.initials: N
authors.lastname: Zhang
authors.forename: Norikazu
authors.initials: N
authors.lastname: Yabuta
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nojima
authors.forename: Duojia
authors.initials: D
authors.lastname: Pan
authors.forename: Junichi
authors.initials: J
authors.lastname: Sadoshima
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018797:Cell Cycle Proteins; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D002908:Chronic Disease; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006579:Heterozygote; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D016877:Oxidants / Q000494:pharmacology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D009124:Muscle Proteins; D016877:Oxidants; D010750:Phosphoproteins; D020033:Protein Isoforms; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D006861:Hydrogen Peroxide