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UBC Theses and Dissertations

Effect of exercise on conduit and resistance artery function in the db/db model of type 2 diabetes Moien Afshari, Farzad


Vasculopathy is the major cause of cardiovascular complications leading to mortality in diabetes mellitus. The earliest stage for diabetic vasculopathy is endothelial dysfunction, which is related to increased oxidative stress. Another abnormality in diabetic vasculature is an increased contractile response to α-adrenergic stimulation, which may lead to hypertension and accelerated atherosclerosis. Exercise decreases diabetic vascular complications with poorly identified mechanisms. The tested hypothesis was that exercise, independent of weight loss and glycemic control, prevents endothelial dysfunction in type 2 diabetes mellitus via a decrease in oxidative stress due to increased antioxidant defense mechanisms. In this study, the mechanisms whereby low- and moderate-intensity aerobic exercise i) improve endothelial function and ii) alter vasoconstrictive response to adrenergic stimulation were assessed in db/db mice. Moderate-intensity exercise lowered body weight, increased mitochondrial SOD (Mn-SOD) and both total and phosphorylated (Ser1177) endothelial nitric oxide synthase (eNOS) protein production; it also decreased plasma (8-isoprostane) and aortic oxidative stress (nitrotyrosine and protein carbonyl levels). Low-intensity exercise did not alter body weight; however, it upregulated cytosolic Cu,Zn-SOD instead of Mn-SOD, and still demonstrated all the above benefits in the db/db aortae. Importantly, both exercise protocols improved endothelial function without altering hyperglycaemic status in db/db mice. In coronary arteries, smooth muscle contractile responses to U-46619 (a thromboxane agonist) or to increases in transmural pressure were not altered in diabetes mellitus. Moderate-exercise restored endothelium-dependent vasodilatation in coronary arteries of db/db mice, accompanied by increased expression of Mn-SOD and decreased nitrotyrosine levels in the hearts. The maximal force generated by phenylephrine was greater in db/db aortae and exercise did not attenuate the response. PKC inhibition normalized the augmented phenylephrine-induced vasoconstriction in db/db to that observed in WT mice. PKC activation, independent of exercise produced greater vasoconstrictor responses in db/db compared to WT mice. In conclusion exercise reversed diabetic endothelial dysfunction independently of improvements in body weight or hyperglycaemia in association with upregulation of eNOS and specific SOD isoforms. Vascular benefits of moderate exercise were independent of changes in myogenic tone. The augmented adrenergic-mediated vasoconstriction in db/db mice was likely due to increased PKC activity that was not affected by exercise.

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