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

View Article: PubMed Central - PubMed

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.

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Apoptosis and hypoxic areas in diabetic and non-diabetic atherosclerosis.A. Representative double immunofluorescence staining of hypoxic areas and apoptotic cells in diabetic and non-diabetic atherosclerosis. Images are stained with fluorescein isothiocyanate-labeled anti-BrdU antibody (green), Dylight™549 fluorophore-labeled anti-pimonidazole antibody (red), and merged. B. Numbers of apoptotic cells in diabetic and non-diabetic atherosclerosis (Mann-Whitney U-test).
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pone.0175976.g006: Apoptosis and hypoxic areas in diabetic and non-diabetic atherosclerosis.A. Representative double immunofluorescence staining of hypoxic areas and apoptotic cells in diabetic and non-diabetic atherosclerosis. Images are stained with fluorescein isothiocyanate-labeled anti-BrdU antibody (green), Dylight™549 fluorophore-labeled anti-pimonidazole antibody (red), and merged. B. Numbers of apoptotic cells in diabetic and non-diabetic atherosclerosis (Mann-Whitney U-test).

Mentions: We determined numbers of apoptotic cells in atherosclerotic lesions using TUNEL assays. Double immunofluorescence emission revealed significantly more apoptotic cells in hypoxic (pimonidazole-positive) areas of atherosclerotic lesions from diabetic, than non-diabetic rabbits (Fig 6A and 6B, S4 Table). The number of apoptotic cells significantly correlated with the vascular area (r = 0.64, p<0.001) and macrophage area (r = 0.46, p<0.05) in non-diabetic atherosclerotic arteries, but not in diabetic atherosclerotic arteries (vascular area, r = 0.004, p = 0.98, macrophage area, r = -0.75, p = 0.70). The result suggests the difference in contributing factors for apoptotic cell death in diabetic and non-diabetic atherosclerotic arteries.


Altered glucose metabolism and hypoxic response in alloxan-induced diabetic atherosclerosis in rabbits
Apoptosis and hypoxic areas in diabetic and non-diabetic atherosclerosis.A. Representative double immunofluorescence staining of hypoxic areas and apoptotic cells in diabetic and non-diabetic atherosclerosis. Images are stained with fluorescein isothiocyanate-labeled anti-BrdU antibody (green), Dylight™549 fluorophore-labeled anti-pimonidazole antibody (red), and merged. B. Numbers of apoptotic cells in diabetic and non-diabetic atherosclerosis (Mann-Whitney U-test).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5391952&req=5

pone.0175976.g006: Apoptosis and hypoxic areas in diabetic and non-diabetic atherosclerosis.A. Representative double immunofluorescence staining of hypoxic areas and apoptotic cells in diabetic and non-diabetic atherosclerosis. Images are stained with fluorescein isothiocyanate-labeled anti-BrdU antibody (green), Dylight™549 fluorophore-labeled anti-pimonidazole antibody (red), and merged. B. Numbers of apoptotic cells in diabetic and non-diabetic atherosclerosis (Mann-Whitney U-test).
Mentions: We determined numbers of apoptotic cells in atherosclerotic lesions using TUNEL assays. Double immunofluorescence emission revealed significantly more apoptotic cells in hypoxic (pimonidazole-positive) areas of atherosclerotic lesions from diabetic, than non-diabetic rabbits (Fig 6A and 6B, S4 Table). The number of apoptotic cells significantly correlated with the vascular area (r = 0.64, p<0.001) and macrophage area (r = 0.46, p<0.05) in non-diabetic atherosclerotic arteries, but not in diabetic atherosclerotic arteries (vascular area, r = 0.004, p = 0.98, macrophage area, r = -0.75, p = 0.70). The result suggests the difference in contributing factors for apoptotic cell death in diabetic and non-diabetic atherosclerotic arteries.

View Article: PubMed Central - PubMed

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-1&alpha;, 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-1&alpha; 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.

No MeSH data available.


Related in: MedlinePlus