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Activation of p38 mitogen-activated protein kinase abolishes insulin-mediated myocardial protection against ischemia-reperfusion injury

¹Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System; ²Endocrine Biology Program, the Hamner Institutes for Health Sciences; and ³Department of Surgery, University of Virginia Health System, Charlottesville, Virginia

Submitted 4 September 2007 ; accepted in final form 9 November 2007

Myocardial ischemia-reperfusion injury contributes significantly to morbidity and mortality in patients with diabetes. Insulin decreases myocardial infarct size in animals and the rate of apoptosis in cultured cells. Ischemia-reperfusion activates p38 mitogen-activated protein kinase (MAPK), which regulates cellular apoptosis. To examine whether p38 MAPK affects insulin's cardioprotection against ischemia-reperfusion injury, we studied overnight-fasted adult male rats by use of an in vivo rat model of myocardial ischemia-reperfusion. A euglycemic clamp (3 mU·min^–1·kg^–1) was begun either 10 min before ischemia (Insulin_BI), 5 min before reperfusion (Insulin_BR), or 30 min after the onset of reperfusion (Insulin_AR), and continued until the end of the study. Compared with saline control, insulin decreased the infarct size in both Insulin_BI (P < 0.001) and Insulin_BR (P < 0.02) rats but not in Insulin_AR rats. The ischemic area showed markedly increased phosphorylation of p38 MAPK compared with the nonischemic area in saline animals. Acute activation of p38 MAPK with anisomycin (2 mg/kg iv 10 min before ischemia) had no effect on infarct size in saline rats. However, it completely abolished insulin's protective effect in Insulin_BI and Insulin_BR rats. Activation of p38 MAPK by anisomycin was associated with marked and persistent elevation in IRS-1 serine phosphorylation. Treatment of animals with SB-239063, a potent and specific inhibitor of p38 MAPK, 10 min before reperfusion enabled insulin-mediated myocardial protection in Insulin_AR rats. We conclude that insulin protects myocardium against ischemia-reperfusion injury when given prior to ischemia or reperfusion, and activation of p38 MAPK abolishes insulin's cardioprotective effect.

insulin; myocardial infarction; anisomycin

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