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Overexpression of heat shock protein 70 improves cardiac remodeling and survival in protein phosphatase 2a-expressing transgenic mice with chronic heart failure

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journal contribution
posted on 07.01.2022, 03:45 by S Yoon, U Gergs, Julie McMullenJulie McMullen, GH Eom
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.

Funding

This research was supported by the National Research Foundation of Korea funded by the Korean government (grant Nos. NRF-2019R1C1C1004521 and NRF-2019R1I1A1A01058992).

History

Publication Date

01/11/2021

Journal

Cells

Volume

10

Issue

11

Article Number

10113180

Pagination

12p.

Publisher

MDPI

ISSN

2073-4409

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