Altered glucose metabolism and hypoxic response in alloxan-induced diabetic atherosclerosis in rabbits

Abstract

Diabetes mellitus accelerates atherosclerosis that causes most cardiovascular events. Several metabolic pathways are considered to contribute to the development of atherosclerosis, but comprehensive metabolic alterations to atherosclerotic arterial cells remain unknown. The present study investigated metabolic changes and their relationship to vascular histopathological changes in the atherosclerotic arteries of rabbits with alloxan-induced diabetes. Diabetic atherosclerosis was induced in rabbit ilio-femoral arteries by injecting alloxan (100 mg/kg), injuring the arteries using a balloon, and feeding with a 0.5% cholesterol diet. We histologically assessed the atherosclerotic lesion development, cellular content, pimonidazole positive-hypoxic area, the nuclear localization of hypoxia-inducible factor-1α, and apoptosis. We evaluated comprehensive arterial metabolism by performing metabolomic analyses using capillary electrophoresis-time of flight mass spectrometry. We evaluated glucose uptake and its relationship to vascular hypoxia using 18F-fluorodeoxyglucose and pimonidazole. Plaque burden, macrophage content, and hypoxic areas were more prevalent in arteries with diabetic, than non-diabetic atherosclerosis. Metabolomic analyses highlighted 12 metabolites that were significantly altered between diabetic and non-diabetic atherosclerosis. A half of them were associated with glycolysis metabolites, and their levels were decreased in diabetic atherosclerosis. The uptake of glucose evaluated as 18F-fluorodeoxyglucose in atherosclerotic lesions increased according to increased macrophage content or hypoxic areas in non-diabetic, but not diabetic rabbits. Despite profound hypoxic areas, the nuclear localization of hypoxia-inducible factor-1α decreased and the number of apoptotic cells increased in diabetic atherosclerotic lesions. Altered glycolysis metabolism and an impaired response to hypoxia in atherosclerotic lesions under conditions of insulin-dependent diabetes might be involved in the development of diabetic atherosclerosis.

Recent advances in capillary electrophoresis‐mass spectrometry: Instrumentation, methodology and applications

“…Rodents, rats and mice mainly, are frequently used as model organisms for basic research on metabolism. Metabolic profiling was performed on rodent muscle , heart , liver , brain , intestinal and glioma tissue, arterial cells as well as on rodent serum/plasma , urine and feces . CE‐MS was furthermore used for research on the metabolism of microorganism , plants and mushroom .…”

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“…It should be noted that according to the literary data glucose level in the blood of animals with alloxaninduced diabetic rat models depends on the individual dose and the method of administration of alloxan (intravenous, intraperitoneal, subcutaneously). According to different literary evidence intraperitoneal administration in the following doses: 100 mg/kg 24,25 , 150 mg/kg 26 , 160-170 mg/kg 20,27 200 mg/kg 28,29,30 of body weight in different solvents are preferred, which are the models to study a long-term toxic action of the drug. As a rule, purified water, 0.9% NaCl solution and acetate buffer (pH=4.5) are used as solvents to prepare alloxan for injections.…”

“…Interestingly, the inhibition of glucokinase is achieved by the one-minute influence of the alloxan. The interaction of alloxan and glucokinase occurs with the formation of disulfide bonds, resulting in inactivation of the enzyme 25,38 .…”

Indoleamine 2,3‐dioxygenase 1 in coronary atherosclerotic plaque enhances tissue factor expression in activated macrophages

“…The Tampere Vascular Study found that IDO1 expression is elevated in the macrophage‐rich cores of advanced atherosclerotic lesions 25. Levels of Kyn that reflect IDO1 activity are increased in human unstable plaques26 and in rabbit macrophage‐rich atherosclerotic arteries 27. In addition, IDO1 activity in blood significantly and positively correlates with more advanced degrees of atherosclerosis 28.…”

“…25 Levels of Kyn that reflect IDO1 activity are increased in human unstable plaques 26 and in rabbit macrophage-rich atherosclerotic arteries. 27 In addition, IDO1 activity in blood significantly and positively correlates with more advanced degrees of atherosclerosis. 28 These findings collectively suggest that the IDO1-mediated Kyn pathway plays a significant role in atherosclerotic lesions.…”