The alteration of Hippo/YAP signaling in the development of hypertrophic cardiomyopathy.

Abstract:

:Hypertrophic cardiomyopathy (HCM) is a leading cause of heart failure and sudden death in adolescents and young adults. Recently, the role of the Hippo/YAP pathway has been investigated in the pathogenesis of HCM, although the detailed molecular mechanisms largely remain elusive. In this study, we demonstrated an up-regulation of YAP mRNA and protein levels in both HCM patient samples and transverse aortic constriction murine models as well as reduced phosphorylation of YAP at serine 127 accompanied by increased transcription of YAP-mediated genes in hypertrophic heart tissues. The cardiomyocyte-specific transgene of human YAP induced cardiac hypertrophy and increased fetal gene expression in the heart. In primary cultured murine cardiomyocytes, ectopic expression of YAP resulted in increased cellular size, whereas the knockdown of YAP reduced the cell size induced by phenylephrine treatment. Interestingly, both mRNA and protein levels of MST1, the kinase upstream of YAP, were dramatically decreased. Further experiments showed that transcription factor FOXO3 binds to the MST1 promoter and that the PI3 K/Akt/FOXO3 signaling pathway regulates MST1 expression. Our findings define the alteration of the Hippo/YAP pathway in the development of HCM. The exploitation of this pathway may provide a novel therapeutic avenue for this disease.

journal_name

Basic Res Cardiol

authors

Wang P,Mao B,Luo W,Wei B,Jiang W,Liu D,Song L,Ji G,Yang Z,Lai YQ,Yuan Z

doi

10.1007/s00395-014-0435-8

subject

Has Abstract

pub_date

2014-01-01 00:00:00

pages

435

issue

5

eissn

0300-8428

issn

1435-1803

journal_volume

109

pub_type

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