Obesity and body fat distribution induce endothelial dysfunction by oxidative stress - Protective effect of vitamin C

Endothelial dysfunction has been reported in obese subjects, but its mechan ism has not been elucidated. We have therefore investigated 1) the possible relationship among BMI, waist-to-hip ratio (WHR), and endothelium-dependen t vasodilation and 2) whether oxidative stress participates in endothelial dysfunction. We recruited 76 healthy subjects (50 men and 26 women aged 21- 45 years) and measured their BMI (kg/m(2)), WHR, and insulin resistance (IR ) estimated by the homeostasis model assessment (HOMA). Endothelium-depende nt and -independent vasodilation were assessed by increasing doses of acety lcholine (ACh) (7.5, 15, and 30 mug . ml(-1) . min(-1)) and sodium nitropru sside (SNP) (0.8, 1.6, and 3.2 mug . ml(-1) . min(-1)) during saline and vi tamin C coinfusion (24 mg/min). The effects of cyclooxygenase activity were evaluated by a dose-response curve to intrabrachial coinfusion of ACh and indomethacin (500 mug/min). Three different groups have been identified acc ording to their BMI: group A (BMI <25), consisting of 10 men and 5 women; g roup B (BMI between 25 and 29), consisting of 16 men and 8 women; and group C (BMI <greater than or equal to>30), consisting of 24 men and 13 women. O bese subjects had significantly lower forearm blood flow (FBF) during ACh i nfusions (means +/- SD): 19.8 +/- 2.8, 10.8 +/- 2.7, and 6.5 +/- 1.8 ml . 1 00 ml(-1) tissue . min(-1) (P < 0.0001) for groups A, B, and C, respectivel y. SNP caused comparable increments in FBF in all groups. Regression analys is revealed a significant negative correlation between BMI (r = -0.676, P < 0.0001), WHR (r = -0.631, P < 0.0001), fasting insulin (r = -0.695, P < 0. 0001), HOMA-IR (r = -0.633, P < 0.0001), and percent peak increase in FBF d uring ACh infusion. In obese subjects, both vitamin C and indomethacin incr eased the impaired vasodilating response to ACh, whereas the SNP effect was unchanged. In conclusion, in obese subjects, ACh-stimulated vasodilation i s blunted, and the increase in FBF is inversely related to BMI, WHR, fastin g insulin, and HOMA-IR. The effects of both vitamin C and indomethacin on i mpaired ACh-stimulated vasodilation support the hypothesis that oxidative s tress contributes to endothelial dysfunction in human obesity.