Long-Term Overexpression of Hsp70 Does Not Protect against Cardiac Dysfunction and Adverse Remodeling in a MURC Transgenic Mouse Model with Chronic Heart Failure and Atrial Fibrillation.

Bianca C Bernardo,Geeta Sapra,Tomomi Ueyama,Helen Kiriazis,Julie R Mcmullen,Natalie L Patterson,Mark A Febbraio,Nelly Cemerlang,Guo-Chang Fan

doi:10.1371/journal.pone.0145173

Abstract

Previous animal studies had shown that increasing heat shock protein 70 (Hsp70) using a transgenic, gene therapy or pharmacological approach provided cardiac protection in models of acute cardiac stress. Furthermore, clinical studies had reported associations between Hsp70 levels and protection against atrial fibrillation (AF). AF is the most common cardiac arrhythmia presenting in cardiology clinics and is associated with increased rates of heart failure and stroke. Improved therapies for AF and heart failure are urgently required. Despite promising observations in animal studies which targeted Hsp70, we recently reported that increasing Hsp70 was unable to attenuate cardiac dysfunction and pathology in a mouse model which develops heart failure and intermittent AF. Given our somewhat unexpected finding and the extensive literature suggesting Hsp70 provides cardiac protection, it was considered important to assess whether Hsp70 could provide protection in another mouse model of heart failure and AF. The aim of the current study was to determine whether increasing Hsp70 could attenuate adverse cardiac remodeling, cardiac dysfunction and episodes of arrhythmia in a mouse model of heart failure and AF due to overexpression of Muscle-Restricted Coiled-Coil (MURC). Cardiac function and pathology were assessed in mice at approximately 12 months of age. We report here, that chronic overexpression of Hsp70 was unable to provide protection against cardiac dysfunction, conduction abnormalities, fibrosis or characteristic molecular markers of the failing heart. In summary, elevated Hsp70 may provide protection in acute cardiac stress settings, but appears insufficient to protect the heart under chronic cardiac disease conditions.

Highlights

Heat shock proteins (Hsps) are endogenous proteins that are upregulated by a wide range of stress conditions, and have been considered potential therapeutic targets in cardiac disease [1,2,3]
Transgenic expression of Muscle-Restricted Coiled-Coil (MURC) was previously shown to increase RhoA signaling in the heart [25], and this was confirmed in MURC and MURC-heat shock protein 70 (Hsp70) Tg mice (Fig 1A)
HSP70 expression tended to be higher in atria (~2.1 fold, not significant) and ventricle (~8.3 fold, P

Summary

Introduction

Heat shock proteins (Hsps) are endogenous proteins that are upregulated by a wide range of stress conditions, and have been considered potential therapeutic targets in cardiac disease [1,2,3]. The best recognized function of Hsps is acting as intracellular chaperones for other proteins, playing an essential role for correct protein function (via folding and correct protein conformational shape), and preventing unwanted protein aggregation which occurs with aging and in settings of cardiac stress [4, 5]. The most conserved and best studied class of all heat shock proteins is the 70kDa family [2]. This study focuses on the most abundant and well characterized stress-inducible isoform of the 70kDa family which we have referred to as Hsp ( known as Hsp). A number of earlier animal studies had suggested that increasing Hsp in the heart provides protection in settings of ischemia and atrial fibrillation (AF). Clinical based research had provided evidence to link Hsp expression in human cardiac tissue with protection against AF. Given current treatments have limited efficacy, dangerous side effects, and poor compliance [19,20,21], investigations into new approaches are urgently required

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