Moien-Afshari F, Ghosh S, Elmi S, Rahman M M, Sallam N, Khazaei M, Kieffer T J, Brownsey R W, Laher I
Department of Pharmacology and Therapeutics, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada.
Diabetologia. 2008 Jul;51(7):1327-37. doi: 10.1007/s00125-008-0996-x. Epub 2008 Apr 25.
AIMS/HYPOTHESIS: Exercise ameliorates oxidative stress-mediated diabetic vascular endothelial dysfunction through poorly defined mechanisms. We hypothesised that, in addition to improving metabolic parameters, upregulation of antioxidants such as superoxide dismutase (SOD) mediates exercise-induced reductions of oxidative stress and increased nitric oxide (NO) bioavailability, and also restores vasodilatation.
Type 2 diabetic db/db and normoglycaemic wild-type mice were exercised at moderate intensity for 1 h a day for 7 weeks, leading to a 10% body weight loss. Sedentary animals or those undergoing a low-intensity exercise regimen causing non-significant weight loss were also used. We examined aortic endothelial cell function, NO bioavailability and various biomarkers of oxidative stress.
Moderate-intensity exercise lowered body weight, increased mitochondrial manganese SOD (MnSOD) and both total and phosphorylated (Ser1177) endothelial nitric oxide synthase (eNOS) protein production; it also reduced whole-body (plasma 8-isoprostane) and tissue oxidative stress (nitrotyrosine immunostaining or protein carbonyl levels in the aorta). Low-intensity exercise did not alter body weight; however, it upregulated cytosolic Cu/Zn-SOD instead of MnSOD, and still demonstrated all the above benefits in the db/db aorta. Importantly, both exercise protocols improved endothelial-dependent vasodilatation and NO bioavailability without altering hyperglycaemic status in db/db mice.
CONCLUSIONS/INTERPRETATION: Exercise reverses diabetic vascular endothelial dysfunction independently of improvements in body weight or hyperglycaemia. Our data suggest that upregulation of eNOS and specific SOD isoforms could play important roles in improving NO bioavailability, as well as in reversing endothelial dysfunction in type 2 diabetes patients through lifestyle modifications in the management of diabetes.
目的/假设：运动可通过尚不明确的机制改善氧化应激介导的糖尿病血管内皮功能障碍。我们推测，除了改善代谢参数外，超氧化物歧化酶（SOD）等抗氧化剂的上调介导了运动诱导的氧化应激降低和一氧化氮（NO）生物利用度增加，并且还恢复了血管舒张功能。
将2型糖尿病db/db小鼠和血糖正常的野生型小鼠每天进行1小时的中等强度运动，持续7周，导致体重减轻10%。还使用了久坐不动的动物或进行低强度运动方案但体重减轻不显著的动物。我们检测了主动脉内皮细胞功能、NO生物利用度以及氧化应激的各种生物标志物。
中等强度运动降低了体重，增加了线粒体锰超氧化物歧化酶（MnSOD）以及总内皮型一氧化氮合酶（eNOS）和磷酸化（Ser1177）eNOS蛋白的产生；它还降低了全身（血浆8-异前列腺素）和组织氧化应激（主动脉中的硝基酪氨酸免疫染色或蛋白质羰基水平）。低强度运动没有改变体重；然而，它上调了胞质铜/锌超氧化物歧化酶（Cu/Zn-SOD）而非MnSOD，并且在db/db小鼠的主动脉中仍表现出上述所有益处。重要的是，两种运动方案均改善了db/db小鼠的内皮依赖性血管舒张和NO生物利用度，而未改变其高血糖状态。
结论/解读：运动可独立于体重或高血糖的改善而逆转糖尿病血管内皮功能障碍。我们的数据表明，eNOS和特定SOD同工型的上调可能在改善NO生物利用度以及通过糖尿病管理中的生活方式改变来逆转2型糖尿病患者的内皮功能障碍方面发挥重要作用。
