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

Somy Yoon,Ulrich Gergs,Gwang Hyeon Eom,Julie R Mcmullen

doi:10.3390/cells10113180

Abstract

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.

Highlights

Heart failure is a complicated, progressive clinical syndrome that results from impairment of either ventricular filling or ejection of blood
Using our previous experimental model, we observed that HSP70 blocked phosphatase 2 catalytic subunit A (PP2CA)-induced negative regulation in the development of cardiac hypertrophy [20]
The double transgenic mice, which express both HSP70 and PP2CA, showed significantly retarded deterioration of ejection fraction (EF) when observations, we wondered whether specific expression of HSP70 in the heart could alleviate PP2CA-induced chronic heart failure

Summary

Introduction

Heart failure is a complicated, progressive clinical syndrome that results from impairment of either ventricular filling (diastole) or ejection of blood (systole). It is widely accepted that the main cause of systolic heart failure or HFrEF is a loss of myocardial tissue due to ischemic heart disease or myocardial infarction [1,2]. As the heart supplies oxygen and nutrition to the periphery by pumping blood, failing hearts tend to compensate for inadequate hemodynamic demands by increasing chamber size and ventricular volume [3,4]. The remodeling of the heart chamber is initially beneficial, heart function gradually worsens, which in turn leads to permanent and irreversible deterioration remodeling known as dilated cardiomyopathy (DCMP) [5]. There are no available therapeutics for DCMP [6]

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