Abstract
BackgroundDifferent mechanisms of diabetic-induced NO dysfunction have been proposed and central to most of them are significant changes in eNOS function as the rate-limiting step in NO bioavailability. eNOS exists in both monomeric and dimeric conformations, with the dimeric form catalyzing the synthesis of nitric oxide, while the monomeric form catalyzes the synthesis of superoxide (O2-). Diabetic-induced shifts to decrease the dimer:monomer ratio is thought to contribute to the degradation of nitric oxide (NO) bioavailability. Exercise has long been useful in the management of diabetes. Although exercise-induced increases expression of eNOS has been reported, it is unclear if exercise may alter the functional coupling of eNOS.MethodsTo investigate this question, Goto-Kakizaki rats (a model of type II diabetes) were randomly assigned to a 9-week running program (train) or sedentary (sed) groups.ResultsExercise training significantly (p < .05) increased plantaris muscle cytochrome oxidase, significantly improved glycosylated hemoglobin (sed: 7.33 ± 0.56%; train: 6.1 ± 0.18%), ad improved insulin sensitivity. Exercise increased both total eNOS expression and the dimer:monomer ratio in the left ventricle LV (sed: 11.7 ± 3.2%; train: 41.4 ± 4.7%). Functional analysis of eNOS indicated that exercise induced significant increases in nitric oxide (+28%) production and concomitant decreases in eNOS-dependent superoxide (-12%) production. This effect was observed in the absence of tetrahydrobiopterin (BH4), but not in the presence of exogenous BH4. Exercise training also significantly decreased NADPH-dependent O2- activity.ConclusionExercise-induced increased eNOS dimerization resulted in an increased coupling of the enzyme to facilitate production of NO at the expense of ROS generation. This shift that could serve to decrease diabetic-related oxidative stress, which should serve to lessen diabetic-related complications.
Highlights
Different mechanisms of diabetic-induced NO dysfunction have been proposed and central to most of them are significant changes in endothelial nitric oxide synthase (NOS) (eNOS) function as the rate-limiting step in NO bioavailability. eNOS exists in both monomeric and dimeric conformations, with the dimeric form catalyzing the synthesis of nitric oxide, while the monomeric form catalyzes the synthesis of superoxide (O2-)
In the present study using a lower intensity of exercise training, we did not observe a change in left ventricular α-MHC protein or α-MHCmRNA levels
The exercise trained GK rats had a significant decrease in fasting blood glucose and consistent with this, a significant decrease in HbA1c (Table 1)
Summary
Different mechanisms of diabetic-induced NO dysfunction have been proposed and central to most of them are significant changes in eNOS function as the rate-limiting step in NO bioavailability. eNOS exists in both monomeric and dimeric conformations, with the dimeric form catalyzing the synthesis of nitric oxide, while the monomeric form catalyzes the synthesis of superoxide (O2-). Chronic exercise increases NO production as early as one week after the start of training [4] These changes are thought to be the result of increased eNOS protein [5,6]. Training effects may be limited to the vasculature of the working muscles; no effect was observed in mesenteric arterioles, suggesting that exercise-induced increases in stress may have be the responsible mechanism [7]. Several groups have reported that shear stress induces increases in eNOS expression [8,9] Studies in both diabetic patients and in diabetic animals have yielded different results; that vascular beds not participating in the response to exercise demonstrate significant improvements, suggesting that mechanisms other than localized stimuli are important [10,11]
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