Document Detail


Yes-associated protein isoform 1 (Yap1) promotes cardiomyocyte survival and growth to protect against myocardial ischemic injury.
MedLine Citation:
PMID:  23275380     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Dominic P Del Re; Yanfei Yang; Noritsugu Nakano; Jaeyeaon Cho; Peiyong Zhai; Takanobu Yamamoto; Nailing Zhang; Norikazu Yabuta; Hiroshi Nojima; Duojia Pan; Junichi Sadoshima
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-12-30
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  288     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-02-11     Completed Date:  2013-04-19     Revised Date:  2014-02-13    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3977-88     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adaptor Proteins, Signal Transducing / genetics,  metabolism*
Animals
Apoptosis*
Cardiomegaly / genetics,  metabolism*,  pathology
Cell Survival / genetics
Cells, Cultured
Chronic Disease
Gene Expression Regulation / drug effects,  genetics
Heterozygote
Hydrogen Peroxide / pharmacology
Mice
Mice, Transgenic
Muscle Proteins / genetics,  metabolism*
Myocardial Ischemia / metabolism*,  pathology
Myocardium / metabolism*,  pathology
Myocytes, Cardiac / metabolism*,  pathology
Oxidants / pharmacology
Phosphoproteins / genetics,  metabolism*
Protein Isoforms / metabolism
Grant Support
ID/Acronym/Agency:
AG27211/AG/NIA NIH HHS; HL59139/HL/NHLBI NIH HHS; HL67724/HL/NHLBI NIH HHS; HL69020/HL/NHLBI NIH HHS; HL91469/HL/NHLBI NIH HHS; R01 AG023039/AG/NIA NIH HHS; R01 HL067724/HL/NHLBI NIH HHS; R01 HL091469/HL/NHLBI NIH HHS; R01 HL102738/HL/NHLBI NIH HHS; R01 HL112330/HL/NHLBI NIH HHS; R21 AG042678/AG/NIA NIH HHS; //Howard Hughes Medical Institute
Chemical
Reg. No./Substance:
0/Adaptor Proteins, Signal Transducing; 0/Muscle Proteins; 0/Oxidants; 0/Phosphoproteins; 0/Protein Isoforms; 0/Yap protein, mouse; BBX060AN9V/Hydrogen Peroxide
Comments/Corrections

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