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

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.

Effects of heme oxygenase-1 upregulation on isoproterenol-induced myocardial infarction

“…The intercellular-junctions are group of proteins such as connexin 43 (Cx-43) that electrically couple cardiomyocytes for its coordinated depolarization, and its uncoupling has been associated with heart diseases [12]. Also, Hsps are endogenous proteins that act as intracellular chaperones for other proteins through its essential role in protein corrective function (help protein folding and correct its shape), and preventing the unwanted protein aggregations due to the process of aging and in settings of cardiac stress [13]. The most important and best studied class of all Hsps is the 70 kDa (kilodalton) family [13].…”

“…Also, Hsps are endogenous proteins that act as intracellular chaperones for other proteins through its essential role in protein corrective function (help protein folding and correct its shape), and preventing the unwanted protein aggregations due to the process of aging and in settings of cardiac stress [13]. The most important and best studied class of all Hsps is the 70 kDa (kilodalton) family [13]. We postulated that the induction of HO-1 could improve electrical activity of the cardiac muscle through up regulation of Cx-43 and Hsp70 in MI.…”

Heat Shock Protein 70 Protects the Heart from Ischemia/Reperfusion Injury through Inhibition of p38 MAPK Signaling

“…Extracellular Hsp70 induced cardiomyocyte inflammation and decreased contractility via toll-like receptors and nuclear factor-κB in primary cardiomyocytes [40]. Moreover, long-term overexpression of Hsp70 failed to prevent cardiac dysfunction and adverse remodeling following chronic heart failure and atrial fibrillation [41]. In this context, the role of Hsp70 in cardiac I/R injury still remains unclear.…”

Effect of atorvastatin on cardiomyocyte hypertrophy through suppressing MURC induced by volume overload and cyclic stretch

“…A study suggested that pressure overload could induce MURC messenger RNA (mRNA) expression in cardiomyocytes . Overexpression of MURC in a transgenic mouse model led to atrial fibrillation and chronic heart failure . Ogata et al reported that MURC was involved in the cardiac concentric hypertrophy under pressure overload …”

“…9 Overexpression of MURC in a transgenic mouse model led to atrial fibrillation and chronic heart failure. 10 Ogata et al reported that MURC was involved in the cardiac concentric hypertrophy under pressure overload. 11 No conclusive proof has been obtained of how volume overload caused by aortocaval (AV) shunt affects MURC upon hypertrophy in the myocardium.…”