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H₂O₂ activation of HSP25/27 protects desmin from calpain proteolysis in rat ventricular myocytes

Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee

Submitted 15 March 2006 ; accepted in final form 17 March 2007

Ischemia-reperfusion-induced Ca²⁺ overload results in activation of calpain-1 in the heart. Calpain-dependent proteolysis contributes to myocardial dysfunction and cell death. Previously, preischemic treatment with low doses of H₂O₂ was shown to improve postischemic function and reduce myocardial infarct size. Our aim was to determine the mechanism by which H₂O₂ protects the heart. We hypothesized that H₂O₂ causes the activation of p38 MAPK which initiates translocation of heat shock protein 25/27 (HSP25/27) to the myofilament Z disk. We further hypothesized that HSP25/27 shields structural proteins, particularly desmin, from calpain-induced proteolysis. To address this hypothesis, we first determined that an ischemia-reperfusion-induced decrease in desmin content could be blocked by H₂O₂ pretreatment of hearts from rats. We next determined that ventricular myocytes that underwent Ca²⁺ overload also demonstrated a calpain-dependent disruption of desmin that could be reduced by H₂O₂/p38 MAPK activation. Furthermore, myocytes acutely treated with H₂O₂ exhibited a decrease in cleavage of desmin upon exposure to exogenous calpain-1 compared with myocytes not pretreated with H₂O₂. The H₂O₂-induced attenuation of desmin degradation by calpain-1 was blocked by inhibition of p38 MAPK. In a final series of experiments, we demonstrated that cardiac myofilaments exposed to recombinant phosphorylated HSP27, but not nonphosphorylated HSP27, had a significant reduction in the calpain-induced degradation of desmin compared with non-HSP27-treated myofilaments. These findings are consistent with the hypothesis that H₂O₂-induced activation of p38 MAPK and subsequent HSP25/27 translocation attenuates desmin degradation brought about by calpain-1 activation in ischemia-reperfused hearts.

ischemia-reperfusion; isolated heart; heat shock protein 25/27; p38 mitogen-activated protein kinase; actinin; troponin I