Altered glucose metabolism and hypoxic response in alloxan-induced diabetic atherosclerosis in rabbits.
Altered glucose metabolism and hypoxic response in alloxan-induced diabetic atherosclerosis in rabbits.
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DOI：
10.1371/journal.pone.0175976
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Asada Y
中科院分区：
文献类型：
--
作者：
Matsuura Y;Yamashita A;Zhao Y;Iwakiri T;Yamasaki K;Sugita C;Koshimoto C;Kitamura K;Kawai K;Tamaki N;Zhao S;Kuge Y;Asada Y
糖尿病会加速动脉粥样硬化，而动脉粥样硬化会导致大多数心血管事件。几种代谢途径被认为有助于动脉粥样硬化的发展，但动脉粥样硬化动脉细胞的全面代谢变化仍不清楚。本研究探讨了四氧嘧啶诱导的糖尿病兔动脉粥样硬化动脉的代谢变化及其与血管组织病理学变化的关系。兔髂股动脉注射四氧嘧啶(100 mg/kg)，球囊损伤动脉，喂饲0.5%胆固醇饲料，建立糖尿病动脉粥样硬化模型。我们从组织学角度评估了动脉粥样硬化病变的发展、细胞含量、匹莫硝唑阳性缺氧区、低氧诱导因子-1α的核定位以及细胞凋亡。我们通过使用毛细管电泳质谱进行代谢组学分析来评估全面的动脉代谢。我们使用18F-氟代脱氧葡萄糖和匹莫硝唑评估葡萄糖摄取及其与血管缺氧的关系。斑块负荷、巨噬细胞含量和缺氧区在糖尿病动脉粥样硬化患者中比非糖尿病患者更常见。代谢学分析突出了12种代谢物，它们在糖尿病和非糖尿病动脉粥样硬化之间发生了显著变化。其中一半与糖酵解代谢产物有关，在糖尿病动脉粥样硬化中，它们的水平降低。在非糖尿病兔中，根据巨噬细胞含量的增加或缺氧区的增加，而不是糖尿病兔，动脉粥样硬化病变中18F-脱氧葡萄糖的摄取被评估为18F-脱氧葡萄糖的增加。尽管存在深度缺氧区，但糖尿病动脉粥样硬化病变中缺氧诱导因子-1α的核定位减少，凋亡细胞数量增加。胰岛素依赖型糖尿病条件下动脉粥样硬化病变的糖酵解代谢改变和对缺氧的反应受损可能参与了糖尿病动脉粥样硬化的发生。
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.