3-nitrotyrosine and ilomastat

Hyperlipidemia attenuates the cardioprotective effect of preconditioning via unknown mechanisms. We have reported previously that in normolipidemic rats, preconditioning decreased ischemia-induced activation and release of myocardial matrix metalloproteinase (MMP)-2 into the coronary perfusate. Here, we investigated whether hyperlipidemia interferes with the cardioprotective effect of preconditioning through modulation of MMP-2. Hearts isolated from male Wistar rats fed 2% cholesterol-enriched or control chow for 9 weeks were subjected to a preconditioning protocol (three intermittent periods of ischemia/reperfusion of 5-min duration each) or a time-matched nonpreconditioning protocol. This was followed by a test ischemia/reperfusion (30-min ischemia and 120-min reperfusion) in both groups. Preconditioning decreased infarct size in the control but not the cholesterol-fed group. Cardioprotection in the preconditioned control group but not in the cholesterol-fed group was associated with an 18 +/- 3% (p < 0.05) inhibition of test ischemia/reperfusion-induced activation and release of myocardial MMP-2 into the perfusate. Myocardial protein levels of tissue inhibitors of MMPs [tissue inhibitor of metalloproteinases (TIMP)-2 and TIMP-4] were not changed in either group. A reduction of infarct size in nonpreconditioned hearts from both control and cholesterol-fed group was produced by the MMP inhibitor ilomastat at 0.25 microM, a concentration producing MMP-2 inhibition comparable with that of preconditioning in the control group. We conclude that hyperlipidemia blocks preconditioning-induced cardioprotection, hyperlipidemia abolishes preconditioning-induced inhibition of myocardial MMP-2 activation and release, preconditioning-induced inhibition of MMP-2 activation and release is not mediated by TIMPs, and pharmacological inhibition of MMPs produces cardioprotection in both normal and hyperlipidemic rats.

Topics: Animals; Blotting, Western; Cholesterol, Dietary; Diet; Dose-Response Relationship, Drug; Enzyme Inhibitors; Hydroxamic Acids; Hyperlipidemias; Indoles; Ischemic Preconditioning, Myocardial; L-Lactate Dehydrogenase; Male; Matrix Metalloproteinase Inhibitors; Myocardial Infarction; Myocardium; Protease Inhibitors; Rats; Rats, Wistar; Tissue Inhibitor of Metalloproteinase-2; Tissue Inhibitor of Metalloproteinase-4; Tissue Inhibitor of Metalloproteinases; Tyrosine