Overexpression of Heat Shock Protein 70 Improves Cardiac Remodeling and Survival in Protein Phosphatase 2A-Expressing Transgenic Mice with Chronic Heart Failure

Cells

Julie R. McMullen¹  Gwang Hyeon Eom²  Somy Yoon²  Ulrich Gergs³ 

[1] Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia;Department of Pharmacology, Chonnam National University Medical School, Hwasun 58128, Korea;Institute of Pharmacology and Toxicology, Faculty of Medicine, Martin Luther University Halle-Wittenberg, 06097 Halle, Germany;

关键词: post-translational modification;    phosphorylation;    dilated cardiomyopathy;    heart failure;    HSP70;   

DOI  :  10.3390/cells10113180

来源: DOAJ

【 摘 要 】

Heat shock protein (HSP) 70 is a molecular chaperone that regulates protein structure in response to thermal stress. In addition, HSP70 is involved in post-translational modification and is related to the severity of some diseases. Here, we tested the functional relevance of long-lasting HSP70 expression in a model of nonischemic heart failure using protein phosphatase 2 catalytic subunit A (PP2CA)-expressing transgenic mice. These transgenic mice, with cardiac-specific overexpression of PP2CA, abruptly died after 12 weeks of postnatal life. Serial echocardiograms to assess cardiac function revealed that the ejection fraction (EF) was gradually decreased in transgenic PP2CA (TgPP2CA) mice. In addition, PP2CA expression exacerbated systolic dysfunction and LV dilatation, with free wall thinning, which are indicators of fatal dilated cardiomyopathy. Interestingly, simultaneous expression of HSP70 in double transgenic mice (dTg) significantly improved the dilated cardiomyopathy phenotype of TgPP2CA mice. We observed better survival, preserved EF, reduced chamber enlargement, and suppression of free wall thinning. In the proposed molecular mechanism, HSP70 preferentially regulates the phosphorylation of AKT. Phosphorylation of AKT was significantly reduced in TgPP2CA mice but was not significantly lower in dTg mice. Signal crosstalk between AKT and its substrates, in association with HSP70, might be a useful intervention for patients with nonischemic heart failure to suppress cardiac remodeling and improve survival.

【 授权许可】

Unknown