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

J Pharmacol Exp Ther. 2006 Jan;316(1):154-61. doi: 10.1124/jpet.105.091140. Epub 2005 Sep 15.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cholesterol, Dietary / pharmacology
  • Diet
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Hydroxamic Acids
  • Hyperlipidemias / complications
  • Hyperlipidemias / pathology*
  • Indoles / pharmacology
  • Ischemic Preconditioning, Myocardial*
  • L-Lactate Dehydrogenase / metabolism
  • Male
  • Matrix Metalloproteinase Inhibitors*
  • Myocardial Infarction / pathology*
  • Myocardial Infarction / prevention & control*
  • Myocardium / metabolism
  • Protease Inhibitors / metabolism
  • Rats
  • Rats, Wistar
  • Tissue Inhibitor of Metalloproteinase-2 / metabolism
  • Tissue Inhibitor of Metalloproteinases / metabolism
  • Tyrosine / analogs & derivatives
  • Tyrosine / metabolism


  • Cholesterol, Dietary
  • Enzyme Inhibitors
  • Hydroxamic Acids
  • Indoles
  • Matrix Metalloproteinase Inhibitors
  • Protease Inhibitors
  • Tissue Inhibitor of Metalloproteinases
  • tissue inhibitor of metalloproteinase-4
  • Tissue Inhibitor of Metalloproteinase-2
  • 3-nitrotyrosine
  • Tyrosine
  • L-Lactate Dehydrogenase
  • ilomastat