Aortic glutathione metabolic status: time-dependent alterations in fat-fed rabbits

Little is known about the vascular metabolic status of glutathione (GSH), which is crucial in cell antioxidant protection, in experimental conditions like high-fat diet-induced atherosclerosis. This issue was, therefore, investigated in two groups of seven rabbits fed a 0.5% cholesterol-, 5% lard- and 5% peanut oil-enriched diet for 18 and 80 days, which, respectively, raised the plasma values of total cholesterol by factors of about 12 and 37, and those of triglycerides by factors of 3 and 13; rabbits fed a standard diet for the same periods served as controls. Total GSH and the activities of the GSH level-maintaining enzymes glutathione reductase (GSSG-Red), gamma-glutamylcysteine synthetase (gamma-GCS) and gamma-glutamyl transpeptidase (gamma-GT) were specifically assessed in the aortic tissue, which was also assayed for fluorescent damage products of lipid peroxidation (FDPL). Sudan red staining of the aortic intima surface was also performed in two other groups of six controls and six fat-fed rabbits. After 18 days of fat feeding, a significant decrement of aortic GSSG-Red activity, associated with gamma-GCS activation, increased GSH levels and normal gamma-GT activity, was observed; FDPL were only moderately enhanced, and atherosclerotic lesions did not occur. After 80 days of atherogenic diet, aortic GSH content was significantly decreased in concomitance with a marked depression of gamma-GT activity, while GSSG-Red and gamma-GCS activities were not significantly changed with respect to 18 days of fat feeding; FDPL underwent further considerable augmentation, and extensive Sudan red-stained atherosclerotic lesions were evident. Thus, short-term fat feeding induces gamma-GCS-dependent GSH biosynthesis of the rabbit aorta; prolonged high-fat intake and hyperlipidemic burden result instead in vascular gamma-GT dysfunction with GSH depletion, eventually favoring oxidative atherogenic effects.