Role of microtubules in ischemic preconditioning against myocardial infarction

OBJECTIVE: The role of microtubules in ischemic preconditioning (PC) was investigated in isolated perfused rabbit hearts. METHODS: Myocardial infarction was induced by 30-min global ischemia and 2-h reperfusion, and infarct size was expressed as a percentage of the left ventricle (%IS/LV). Using separate groups of rabbits, ventricular biopsies were taken before and after PC for determination of protein kinase C (PKC) translocation and p38-mitogen-activated protein kinase (p38MAP kinase) activation. To depolymerize microtubules, we used two structurally different agents, colchicine (50 microM) and nocodazole (1 microM). RESULTS: PC with two cycles of 5-min ischemia/5-min reperfusion significantly reduced infarct size from 60.1+/-5.0% to 20.0+/-5.0%. Although neither colchicine nor nocodazole modified infarct size in nonpreconditioned hearts, these agents abolished the infarct size-limiting effects of PC (%IS/LV=56.1+/-6.0% and 53.5+/-2.5%, respectively). Colchicine prevented translocation of PKC-epsilon and p38MAP kinase activation by PC. PKC translocation by infusion of 1-oleyl-2-acetyl-sn-glycerol in nonischemic hearts was also prevented by colchicine. CONCLUSION: Microtubules play a crucial role in the development of anti-infarct tolerance by PC as a mechanism supporting translocation of activated PKC.