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 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.
Giricz
Zoltán
Z
Cardiovascular Research Group, Department of Biochemistry, University of Szeged, Dóm tér 9, H-6720 Szeged, Hungary.
Lalu
Manoj M
MM
Csonka
Csaba
C
Bencsik
Péter
P
Schulz
Richard
R
Ferdinandy
Péter
P
D000818:Animals; D015153:Blotting, Western; D002791:Cholesterol, Dietary / Q000494:pharmacology; D004032:Diet; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006877:Hydroxamic Acids; D006949:Hyperlipidemias / Q000150:complications / Q000473:pathology*; D007211:Indoles / Q000494:pharmacology; D019157:Ischemic Preconditioning, Myocardial; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D009203:Myocardial Infarction / Q000473:pathology* / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism; D011480:Protease Inhibitors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D000097792:Tissue Inhibitor of Metalloproteinase-4
D002791:Cholesterol, Dietary; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D007770:L-Lactate Dehydrogenase; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D019716:Tissue Inhibitor of Metalloproteinase-2; D019714:Tissue Inhibitor of Metalloproteinases; D014443:Tyrosine; D000097792:Tissue Inhibitor of Metalloproteinase-4; C002744:3-nitrotyrosine; C119203:ilomastat