Abstract
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 μM, 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.
Footnotes
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This work was supported by the Hungarian Scientific Research Fund (Grant OTKA T046417), by the Hungarian Ministry of Health (Grant ETT 616/2003), by the National Research and Development Program (Grant NKFP 001/2001), and by the North Atlantic Treaty Organization Cooperative Linkage (Grant LST.CLG.976650). M.M.L. was a graduate trainee of the Alberta Heritage Foundation for Medical Research and the Canadian Institutes of Health Research and North Atlantic Treaty Organization visiting student at the University of Szeged. R.S. is a Senior Scholar of the Alberta Heritage Foundation for Medical Research. P.F. holds an István Széchenyi Professorship of the Hungarian Academy of Sciences. For further details, see http:www.cardiovasc.com.
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doi:10.1124/jpet.105.091140.
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ABBREVIATIONS: ONOO–, peroxynitrite; MMP, matrix metalloproteinase; TIMP, tissue inhibitor of metalloproteinases; TTC, triphenyltetrazoliumchloride; LDH, lactate dehydrogenase.
- Received June 16, 2005.
- Accepted September 13, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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