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.

Regulation of Myocardial Cell Growth and Death by the Hippo Pathway

“…5 In addition, human hypertrophic cardiomyopathy patients showed Yap activation in the heart. 87 These results are consistent with the notion that inhibition of the Hippo pathway and activation of Yap may induce cardiac hypertrophy.…”

“…Third, activation of Yap is observed in human patients with hypertrophic cardiomyopathy. 87 In this condition, does inhibition of Yap ameliorate the progression of cardiomyopathy? Because Yap is involved in tumorigenesis, small molecule inhibitors of Yap are being developed.…”

Activated Phosphatidylinositol 3-Kinase/Akt Inhibits the Transition of Endothelial Progenitor Cells to Mesenchymal Cells by Regulating the Forkhead Box Subgroup O-3a Signaling

“…Notablely, phosphorylated FoxO3a by PI3K/Akt signaling, was recently proved to bind the promoter of YAP, and then activated Hippo/YAP signaling [27]. And the activation of Hippo/YAP signaling was previously demonstrated to promote the cytoplasmic translocation of Smad3 from nuleues to relay cell density information in TGF-β-mediated epithelial-tomesenchymal transition [28].…”

The Hippo Pathway in Heart Development, Regeneration, and Diseases

“…In cardiomyocytes cultured in vitro , expression of YAP increased cell size and knockdown of YAP attenuated phenylephrine induced cardiomyocyte hypertrophy 170 . Interestingly, it was recently reported that YAP expression is enhanced while YAP phosphorylation is dampened with reduced Mst1 expression in myocardium of patients with hypertrophic cardiomyopathy 174 , suggesting a role of YAP in pathogenesis of human hypertrophic heart disease. Taken together, functions of YAP and the Hippo pathway in cardiac hypertrophy might be more complex and context-dependent.…”