FOXO1 contributes to diabetic cardiomyopathy via inducing imbalanced oxidative metabolism in type 1 diabetes
FOXO1 contributes to diabetic cardiomyopathy via inducing imbalanced oxidative metabolism in type 1 diabetes
复制标题
FOXO1 通过诱导 1 型糖尿病氧化代谢失衡导致糖尿病心肌病
DOI：
10.1111/jcmm.15418
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发表时间：
2020-05-25
影响因子：
5.3
通讯作者：
Xia, Zhengyuan
中科院分区：
文献类型：
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作者：
Yan, Dan;Cai, Yin;Xia, Zhengyuan
叉头盒蛋白O1 （FOXO1）是一种核转录因子，在糖尿病小鼠心肌中被优选激活。然而，其在非肥胖型胰岛素缺乏型糖尿病中糖尿病性心肌病发展中的作用和机制尚不清楚。我们假设心脏FOXO1过度激活可归因于1型糖尿病患者心肌氧化代谢失衡、线粒体和心功能障碍。将foxo1选择性抑制剂AS1842856给予链脲霉素诱导的糖尿病大鼠，观察其心功能、线粒体酶PDK4和CPT1以及线粒体功能。用1 μ M AS1842856处理非糖尿病对照(C)和D大鼠原代心肌细胞，海马实验测定葡萄糖、棕榈酸酯和丙酮酸酯对心肌细胞生物能量学的影响。结果显示，糖尿病心脏FOXO1核易位升高，并伴有心肌和线粒体功能障碍（表现为mtROS水平升高、线粒体膜电位降低）和细胞凋亡增加（P < 0.05, D vs C）。糖尿病心肌表现为糖酵解、葡萄糖氧化和脂肪酸氧化受损，PDK4和CPT1表达增强。AS1842856减弱或阻止了所有这些变化，除了糖酵解。我们得出结论，FOXO1激活，通过刺激PDK4和CPT1，将底物选择从葡萄糖转移到脂肪酸，并导致线粒体和心脏功能障碍。
Forkhead box protein O1 (FOXO1), a nuclear transcription factor, is preferably activated in the myocardium of diabetic mice. However, its role and mechanism in the development of diabetic cardiomyopathy in non-obese insulin-deficient diabetes are unclear. We hypothesized that cardiac FOXO1 over-activation was attributable to the imbalanced myocardial oxidative metabolism and mitochondrial and cardiac dysfunction in type 1 diabetes. FOXO1-selective inhibitor AS1842856 was administered to streptozotocin-induced diabetic (D) rats, and cardiac functions, mitochondrial enzymes PDK4 and CPT1 and mitochondrial function were assessed. Primary cardiomyocytes isolated from non-diabetic control (C) and D rats were treated with or without 1 mu M AS1842856 and underwent Seahorse experiment to determine the effects of glucose, palmitate and pyruvate on cardiomyocyte bioenergetics. The results showed diabetic hearts displayed elevated FOXO1 nuclear translocation, concomitant with cardiac and mitochondrial dysfunction (manifested as elevated mtROS level and reduced mitochondrial membrane potential) and increased cell apoptosis (all P < .05, D vs C). Diabetic myocardium showed impaired glycolysis, glucose oxidation and elevated fatty acid oxidation and enhanced PDK4 and CPT1 expression. AS1842856 attenuated or prevented all these changes except for glycolysis. We concluded that FOXO1 activation, through stimulating PDK4 and CPT1, shifts substrate selection from glucose to fatty acid and causes mitochondrial and cardiac dysfunction.