H 2 O 2 activation of HSP25/27 protects desmin from calpain proteolysis in rat ventricular myocytes

Bradford C. Blunt, Aaron T. Creek, De Anna C. Henderson, Polly Hofmann

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Ischemia-reperfusion-induced Ca 2+ 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 H 2 O 2 was shown to improve postischemic function and reduce myocardial infarct size. Our aim was to determine the mechanism by which H 2 O 2 protects the heart. We hypothesized that H 2 O 2 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 H 2 O 2 pretreatment of hearts from rats. We next determined that ventricular myocytes that underwent Ca 2+ overload also demonstrated a calpain-dependent disruption of desmin that could be reduced by H 2 O 2 /p38 MAPK activation. Furthermore, myocytes acutely treated with H 2 O 2 exhibited a decrease in cleavage of desmin upon exposure to exogenous calpain-1 compared with myocytes not pretreated with H 2 O 2 . The H 2 O 2 -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 H 2 O 2 -induced activation of p38 MAPK and subsequent HSP25/27 translocation attenuates desmin degradation brought about by calpain-1 activation in ischemia-reperfused hearts.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume293
Issue number3
DOIs
StatePublished - Sep 1 2007

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HSP27 Heat-Shock Proteins
Calpain
Desmin
Muscle Cells
Proteolysis
p38 Mitogen-Activated Protein Kinases
Myofibrils
Ischemia
Reperfusion
Cell Death
Myocardial Infarction

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

H 2 O 2 activation of HSP25/27 protects desmin from calpain proteolysis in rat ventricular myocytes . / Blunt, Bradford C.; Creek, Aaron T.; Henderson, De Anna C.; Hofmann, Polly.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 293, No. 3, 01.09.2007.

Research output: Contribution to journalArticle

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AB - Ischemia-reperfusion-induced Ca 2+ 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 H 2 O 2 was shown to improve postischemic function and reduce myocardial infarct size. Our aim was to determine the mechanism by which H 2 O 2 protects the heart. We hypothesized that H 2 O 2 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 H 2 O 2 pretreatment of hearts from rats. We next determined that ventricular myocytes that underwent Ca 2+ overload also demonstrated a calpain-dependent disruption of desmin that could be reduced by H 2 O 2 /p38 MAPK activation. Furthermore, myocytes acutely treated with H 2 O 2 exhibited a decrease in cleavage of desmin upon exposure to exogenous calpain-1 compared with myocytes not pretreated with H 2 O 2 . The H 2 O 2 -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 H 2 O 2 -induced activation of p38 MAPK and subsequent HSP25/27 translocation attenuates desmin degradation brought about by calpain-1 activation in ischemia-reperfused hearts.

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