Reduced Cardioprotective Action of Adiponectin in High-Fat Diet-Induced Type II Diabetic Mice and Its Underlying Mechanisms
Reduced Cardioprotective Action of Adiponectin in High-Fat Diet-Induced Type II Diabetic Mice and Its Underlying Mechanisms
复制标题
脂联素对高脂饮食诱导的 II 型糖尿病小鼠心脏保护作用的降低及其潜在机制
DOI：
10.1089/ars.2010.3722
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发表时间：
2011-10-01
影响因子：
6.6
通讯作者：
Ma, Xin-Liang
中科院分区：
文献类型：
--
作者：
Yi, Wei;Sun, Yang;Ma, Xin-Liang
糖尿病通过不完全了解的机制加剧了缺血性心脏病的发病率和死亡率。尽管脂联素 (APN) 可减少非糖尿病动物的心肌缺血/再灌注 (MI/R) 损伤，但 APN 的心脏保护作用是否在糖尿病（一种内源性 APN 减少的病理状况）中发生改变尚未得到研究。高脂饮食（HD）诱导的糖尿病小鼠和正常饮食（ND）对照通过冠状动脉结扎进行MI，并在再灌注前10分钟给予载体或APN球状结构域（gAPN，2μg/g）。与 ND 小鼠（gAPN 发挥显着的心脏保护作用）相比，HD 小鼠表现出更大的 MI/R 损伤，并且需要三倍的 gAPN 剂量才能达到 ND 小鼠的心脏保护程度（即梗塞面积、细胞凋亡和心脏功能）。 APN 通过 AMP 激活蛋白激酶 (AMPK) 依赖性代谢调节和 AMPK 独立的抗氧化/抗硝化途径减少 MI/R 损伤。与 ND 相比，HD 小鼠在基础上和 MI/R 后表现出 gAPN 诱导的 AMPK 激活显着减弱（p < 0.05）。尽管低剂量和高剂量 gAPN 均同等地减弱 ND 小鼠中 MI/R 诱导的氧化应激（即 NADPH 氧化酶表达和超氧化物生成）和硝化应激（即诱导型一氧化氮合酶表达、一氧化氮生成和过氧亚硝酸盐形成），但只有高剂量 gAPN 在 HD 小鼠中有效。我们首次证明 HD 诱导的糖尿病会减弱 AMPK 依赖性和 AMPK 独立的 APN 心脏保护作用，表明存在未报告的糖尿病心脏 APN 抵抗。抗氧化剂。氧化还原信号。 15, 1779-1788。
Diabetes exacerbates ischemic heart disease morbidity and mortality via incompletely understood mechanisms. Although adiponectin (APN) reduces myocardial ischemia/reperfusion (MI/R) injury in nondiabetic animals, whether APN's cardioprotective actions are altered in diabetes, a pathologic condition with endogenously reduced APN, has never been investigated. High-fat diet (HD)-induced diabetic mice and normal diet (ND) controls were subjected to MI via coronary artery ligation, and given vehicle or APN globular domain (gAPN, 2 mu g/g) 10 min before reperfusion. Compared to ND mice (where gAPN exerted pronounced cardioprotection), HD mice manifested greater MI/R injury, and a tripled gAPN dose was requisite to achieve cardioprotective extent seen in ND mice (i.e., infarct size, apoptosis, and cardiac function). APN reduces MI/R injury via AMP-activated protein kinase (AMPK)-dependent metabolic regulation and AMPK-independent antioxidative/antinitrative pathways. Compared to ND, HD mice manifested significantly blunted gAPN-induced AMPK activation, basally and after MI/R (p < 0.05). Although both low- and high-dose gAPN equally attenuated MI/R-induced oxidative stress (i.e., NADPH oxidase expression and superoxide production) and nitrative stress (i.e., inducible nitric oxide synthase expression, nitric oxide production, and peroxynitrite formation) in ND mice, only high-dose gAPN efficaciously did so in HD mice. We demonstrate for the first time that HD-induced diabetes diminished both AMPK-dependent and AMPK-independent APN cardioprotection, suggesting an unreported diabetic heart APN resistance. Antioxid. Redox Signal. 15, 1779-1788.