Journal
EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 643, Issue 1, Pages 78-83Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejphar.2010.06.015
Keywords
Ischemic Preconditioning; Glycogen Synthase Kinase-3 beta; Hyperlipidaemia; Mitochondrial Permeability Transition Pore
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Ischemic preconditioning (IPC) produces cardioprotection by phosphorylation of glycogen synthaes kinase-3 beta (GSK-3 beta) that inhibits the opening of mitochondrial permeability transition pore (MPTP), and this cardioprotective action of IPC is attenuated by hyperlipidaemia. The present study investigated the role of GSK-3 beta in attenuation of cardioprotective effect of IPC, by hyperlipidaemia in the rat heart. Hyperlipidaemia was produced in rat by feeding high fat diet for six weeks. Isolated perfused rat heart was subjected to 30 min of ischemia followed by 120 min of reperfusion. Myocardial infarct size was estimated by triphenyltetrazolium chloride (TTC) staining and lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) was analyzed from coronary effluent IPC significantly decreased the myocardial infarct size and the release of LDH and CK-MB from normal rat heart. IPC induced myocardial protection was attenuated in hyperlipidaemic rat heart. However, cardioprotective effect of pharmacological preconditioning with GSK-3 beta inhibitors i.e. Lithium Chloride (LiCl) (20 mM), Indirubin - 3 Monooxime (1 mu M) and 3-(2, 4-dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2, 5-dione (SB216763) (3 mu M), was not attenuated. This differential attenuation by hyperlipidaemia, of IPC and pharmacological preconditioning induced cardioprotection is a new finding in our study. GSK-3 beta inhibition is reported to increase the threshold of opening for MPTP during reperfusion. Administration of atractyloside (20 mu M), an opener of MFTP, significantly attenuated the cardioprotective effect of IPC in normal heart, and pharmacological preconditioning in the hyperlipidaemic rat heart Thus, the attenuation of cardioprotective effect of IPC in hyperlipidaemic heart may be due to inhibition of protective signaling pathways upstream of GSK-3 beta and inhibition of opening of MFTP. (C) 2010 Elsevier B.V. All rights reserved.
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