Stress adaptation of the heart: role of hyperlipidemia and MMP-2

Giricz Zoltán
Stress adaptation of the heart: role of hyperlipidemia and MMP-2.
[Thesis] (Unpublished)

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Abstract in foreign language

Cardiac stress adaptation, i.e. preconditioning, is deteriorated in hyperlipidemia, but the underlying mechanisms are still undiscovered. Bioavailability of a major effector of preconditioning, nitric oxide (NO), is decreased in hyperlipidemia, however, inhibition of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, a key enzyme of the mevalonate pathway (cholesterol synthesis), increases the endothelial NO synthase (eNOS) mRNA level. Release and activation of matrix metalloproteinases (MMPs) contribute to myocardial injury after ischemia/reperfusion, but their role in preconditioning and in the loss of preconditioning in hyperlipidemia is not known. Therefore, here we have studied the role of dietary and pharmacological inhibition of the mevalonate pathway on cardiac NO metabolism in normal and hyperlipidemic animals; and we have looked at the activation and release of MMPs in preconditioning. Moreover, since hyperlipidemia-induced gene expression changes of the rat heart have not been investigated to date, we performed a cDNA microarray study as well. Rats were fed with 2% cholesterol-enriched or normal diet for 9 weeks. Normal and hyperlipidemic animals were treated with farnesol, a major metabolite of the mevalonate pathway, or with lovastatin, a HMG-CoA reductase inhibitor. In separate experiments, isolated hearts of normal and hyperlipidemic rats were subjected to a preconditioning protocol (3x5 min ischemia and reperfusion) followed by 30 min ischemia and 2 h reperfusion, or a time matched non-preconditioning protocol. We have found that hyperlipidemia decreased cardiac NO level, however, dietary or pharmacological inhibition of the mevalonate pathway did not influence cardiac NO metabolism. Neither hyperlipidemia, nor farnesol, or lovastatin affected cardiac NOS activity or eNOS protein level. Preconditioning decreased infarct size and deteriorated release and activation of MMP-2 in normal but not in hyperlipidemic animals. A reduction of infarct size in non-preconditioned hearts from both control and hyperlipidemic group was produced by the MMP inhibitor ilomastat. DNA microarray analysis of 3200 genes revealed that dietary hyperlipidemia up-regulated cardiac expression of 26 genes, while 25 showed down-regulation. Taken together, hyperlipidemia blocks preconditioning-induced cardioprotection, in which enhanced post-ischemic myocardial activation and release of MMP-2 play a significant role. Furthermore, we conclude that pharmacological inhibition of MMPs is a valid option to mimic the cardioprotective effect of preconditioning in both normal and hyperlipidemic animals. Although some genes, expression of which is altered by hyperlipidemia, have been suspected to be related to cardiovascular diseases, none of them have been previously shown to be involved in cardiac effects of the hyperlipidemia. Therefore, our present findings may open new directions in the research of the cardiac effects of hyperlipidemia.

Item Type: Thesis (PhD)
Creators: Giricz Zoltán
Hungarian title label: A MMP-2 aktivációjának szerepe a szív iszkémiás károsodásában és stresszadaptációjában: a hiperkoleszterinémia hatása
Divisions: Doctoral School of Multidisciplinary Medicine
Discipline label: Medicine > Theoretical Medicine
Defence date label: 2006
Item ID: 266
Identification Number: 31139894
Date Deposited: 2010. May. 12. 08:08
Last Modified: 2020. Jan. 24. 13:32
Depository no.: B 4210
Defence/Citable status: Defended.

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