JPET #91140 1 Title Page Hyperlipidemia attenuates the infarct-size limiting effect of ischemic preconditioning: role of matrix metalloproteinase-2 inhibition

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 cholesterolfed 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 TIMP4) 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. This article has not been copyedited and formatted. The final version may differ from this version. JPET Fast Forward. Published on September 15, 2005 as DOI: 10.1124/jpet.105.091140 at A PE T Jornals on A ril 9, 2017 jpet.asjournals.org D ow nladed from