Doctoral Degrees (Physiological Sciences)
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Browsing Doctoral Degrees (Physiological Sciences) by browse.metadata.advisor "Du Toit, Eugene F."
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- ItemDietary red palm oil-supplementation offers cardioprotection against Ischaemia/Reperfusion injury : possible cellular mechanisms involved(Stellenbosch : University of Stellenbosch, 2005-12) Esterhuyse, Adriaan Johannes; Van Rooyen, Jacques; Du Toit, Eugene F.; University of Stellenbosch. Faculty of Science. Dept. of Physiological Sciences.ENGLISH ABSTRACT: Activation of the NO-cGMP pathway is associated with myocardial protection against ischaemia/reperfusion injury. However, high-cholesterol diets alter function of this pathway and these alterations have been implicated in both ischaemic/reperfusion injury and the development of ischaemic heart disease. Little is known about the effects of supplements such as Red Palm Oil (RPO) on the myocardial NO-cGMP-signalling pathway. RPO consists of saturated, mono-unsaturated and poly-unsaturated fatty acids and is rich in antioxidants such as β-carotene and Vitamin E (tocopherols and tocotrienols). The aims of this study were: 1) to determine whether dietary RPO-supplemention protects against ischaemia/reperfusion injury in rats fed a standard rat chow (control) and cholesterol-enriched diets and 2) if so, to investigate possible mechanisms for this protection. Male Long-Evans rats were fed a standard rat chow or a standard rat chow plus cholesterol and/or RPO-supplementation for 6 weeks. Myocardial functional recovery was measured and hearts were freeze-clamped for determination of myocardial phospholipid, cAMP/cGMP concentrations, total myocardial nitric oxide concentrations, lipid hydroperoxide production and superoxide dismutase- and nitric oxide synthase activity in isolated rat hearts subjected to 25 minutes of normothermic total global ischaemia. In addition, the degree of phosphorylation of extracellular signal-regulated kinase (ERK), p38, c-Jun N-terminal protein kinase (JNK) and protein kinase B (PKB/Akt) was investigated. Furthermore, the effect of RPO-supplementation on caspase-3 activation and poly (ADP-ribose) polymerase (PARP)-cleavage in hearts subjected to ischaemia and reperfusion was also investigated. Our data show that dietary RPO-supplementation protects the hearts of rats on a standard rat chow (control) and hypercholesterolaemic diet against ischaemia/reperfusion injury as reflected by improved aortic output recovery. Increased intracellular cardiomyocyte NO concentrations as observed in control hearts supplemented with RPO after 120 minutes hypoxia may contribute to the elevated cGMP concentration and may confer some of the cardioprotection to the ischaemic/reperfused heart. Although improved functional recovery with RPO-supplementation of a high-cholesterol diet was also associated with an increase in intracellular cardiomyocyte NO production after hypoxia compared to the non-hypoxic conditions, it could not be linked to increased NO-cGMP signalling. These data are in agreement with other studies, which showed that high-cholesterol diet impairs NO-cGMP signalling and confirms our hypothesis that elevated cGMP concentrations may not be the only mechanism of protection. We have also shown that RPOsupplementation caused increased phosphorylation of p38 and PKB, reduced phosphorylation of JNK and attenuation of PARP cleavage, which may contribute to the protection of the cell against apoptosis. Based on our results we propose that the myocardial protection offered by RPO-supplementation of rats on a normal and hypercholesterolaemic diet may be associated with either its antioxidant characteristics and/or changes in the fatty acid composition of the myocardium during ischaemia/reperfusion. Furthermore, we demonstrated for the first time that RPO-supplementation protects the isolated perfused working rat heart during reperfusion from ischaemia/reperfusion-induced injury through a MAPK-dependent pathway.