Received for publication July 18, 2005.
Revised September 13, 2005.
Accepted for publication September 13, 2005.

Hyperlipidemia attenuates the infarct-size limiting effect of ischemic preconditioning: role of matrix metalloproteinase-2 inhibition

Abstract

Hyperlipidemia attenuates the cardioprotective effect of preconditioning via unknown mechanisms. We have previously reported that in normolipidemic rats preconditioning decreased ischemia-induced activation and release of myocardial matrix metalloproteinase-2 (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 non-preconditioning 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 a 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 (TIMP-2 and TIMP-4) were not changed in either group. A reduction of infarct size in non-preconditioned hearts from both control and cholesterol-fed group was produced by the MMPs inhibitor ilomastat at 0.25 µM, a concentration producing MMP-2 inhibition comparable to that of preconditioning in the control group. We conclude that: (i) hyperlipidemia blocks preconditioning-induced cardioprotection, (ii) hyperlipidemia abolishes preconditioning-induced inhibition of myocardial MMP-2 activation and release, (iii) preconditioning-induced inhibition of MMP-2 activation and release is not mediated by TIMPs, and (iv) pharmacological inhibition of MMPs produces cardioprotection in both normal and hyperlipidemic rats.

Key words: cholesterol-diet, hyperlipidemia, ilomastat, ischemia, matrix metalloproteinase-2, preconditioning

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