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Myocardial apoptosis in acute diabetes : role of lipotoxicity and oxidative stress Ghosh, Sanjoy

Abstract

The general objective of this thesis was to examine the role of lipotoxicity and oxidative stress under control or high fat fed conditions in acute STZ diabetes. In the lipotoxicity study, we examined the impact of dietary manipulation of palmitic acid on rat cardiomyocyte apoptosis under hyperglycemic conditions in vivo. Feeding palm oil (PO) or sunflower oil (isocaloric control; SO) for 4 weeks induced hyperinsulinemia, with a moderate rise in serum glucose. PO magnified the palmitic acid whereas SO enhanced the linoleic and docosahexaenoic acid content within lipoproteins and heart. Following streptozotocin induced diabetes, total cardiac free fatty ac id (FFA) and palmitic acid remained unchanged in PO rats despite a dramatic increase in serum FFA, and may reflect the activation of compensatory mechanisms that limit excessive accumulation of FFA in the heart. Indeed, lipoprotein lipase activity at the coronary lumen declined in high fat fed diabetic rats. Additional imposition of diabetes in PO animals resulted in the highest level of myocardial apoptosis and lipid peroxidation. Although SO decreased cardiac glutathione maximally following diabetes, lipid peroxidation remained unaltered. Our data suggest that although PO increases cardiac apoptosis, SO with its glutathione lowering and potential enhancement of fatty acid metabolites could also exert detrimental effects on the diabetic heart. In the GSH study, we examined the regulation of GSH and its role in apoptosis and oxidative stress in the acutely diabetic rat heart. Acute diabetes induced changes in mitochondrial membrane potential and increased production of free radicals. Additionally, the role of cytosolic or mitochondrial GSH and its effects on oxidative stress and apoptosis in the acutely diabetic heart was investigated. Although myocardial GSH levels were not altered in diabetes, increasing GSH levels by ~2 fold by exogenous supplementation attenuated the oxidative damage and apoptosis. Thus although total myocardial levels of GSH were unaltered, mitochondrial GSH, that controls both lipid peroxidation and apoptosis may have decreased following diabetes and was reversed by exogenous GSH. To test this hypothesis, we depleted either cytosolic GSH with L-buthionine-[S,R]-sulfoximine (BSO, 4 mmol/kg; 3 days) or /and mitochondrial GSH with diethyl maleate (DEM, 4 mmol/kg; 3 days) following diabetes. Only DEM+BSO treatment augmented the oxidative stress and apoptosis. In conclusion, the oxidative stress and the resultant apoptosis demonstrated in the diabetic heart may probably occur as a consequence of depletion of mitochondrial GSH that can be reversed with exogenous supplementation of GSH.

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