Heat-shock-protein 90 protects from downregulation of HIF-1α in calcineurin-induced myocardial hypertrophy

摘要: Abstract Aim of the study Capillary/myocyte mismatch is a hallmark maladaptive myocardial hypertrophy, but exact mechanisms this phenomenon remain unknown. We therefore aimed to evaluate role calcineurin A in regulation hypoxia-inducible factor-1 alpha (HIF-1 alpha) overexpressing mouse model hypertrophy. Methods and results Mice (CnATg) showed persistent upregulation HIF-1 protein without evidence reduction capillary density despite progressive Likewise, overexpression isolated cardiomyocytes induced protein. In contrast, NFAT-overexpression had no such effect, implying that NFAT-independent were responsible for increased levels. addition, inhibition HSP90 via HSP90-inhibitor 17-AAG or siRNA abolished A-induced alpha. Consequently, target genes like VEGF-A, BNIP-3 PGK-1 was also inhibited by either directed against HSP90. Finally, when CnATg mice treated with 17-AAG, they demonstrated reduced left ventricular function density. Conclusions describe here first time phosphatase prevents development capillary/myocyte This effect mediated HSP-90 stabilization Further work needed understand unexpected cardioprotective A.