Obesity and Body Fat Distribution Induce Endothelial Dysfunction by Oxidative Stress

Abstract

Endothelial dysfunction has been reported in obese subjects, but its mechanism has not been elucidated. We have therefore investigated 1) the possible relationship among BMI, waist-to-hip ratio (WHR), and endothelium-dependent 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-dependent and -independent vasodilation were assessed by increasing doses of acetylcholine (ACh) (7.5, 15, and 30 µg · ml -1 · min -1) and sodium nitroprusside (SNP) (0.8, 1.6, and 3.2 µg · ml -1 · min 19.8 ± 2.8, 10.8 ± 2.7, and 6.5 ± 1.8 ml · 100 ml -1 tissue · min -1 (P < 0.0001) for groups A, B, and C, respectively. SNP caused comparable increments in FBF in all groups. Regression analysis 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 during ACh infusion. In obese subjects, both vitamin C and indomethacin increased the impaired vasodilating response to ACh, whereas the SNP effect was unchanged. In conclusion, in obese subjects, ACh-stimulated vasodilation is blunted, and the increase in FBF is inversely related to BMI, WHR, fasting insulin, and HOMA-IR. The effects of both vitamin C and indomethacin on impaired ACh-stimulated vasodilation support the hypothesis that oxidative stress contributes to endothelial dysfunction in human obesity. O bese subjects are at high risk for developing diabetes, dyslipidemia, hypertension, and cardiovascular diseases, which lead to an increased risk of mortality (1-3). Moreover, it has been demonstrated that obesity is associated with hyperinsulinemia, an independent predictor for coronary artery disease (4). In fact, hyperinsulinemia is linked to insulin resistance (IR) and potentially to atherogenic abnormalities.The normal endothelium plays a key role in the regulation of vascular tone and in preventing the progression of atherosclerosis through the production and release of both contracting and relaxing factors (5). Nitric oxide (NO) represents the major endogenous relaxing factor (6-9), and its production is stimulated by physical stimuli (e.g., shear stress) (9) and by several agonists (e.g., acetylcholine [ACh], bradykinin, substance P, and serotonin) (8). The activation of guanylate cyclase and the subsequent accumulation of cGMP are the main mechanisms of NO-induced vasodilation. In contrast, sodium nitroprusside (SNP) is an endothelium-independent vasodilator capable of inducing vasodilation by providing an inorganic source of NO (10). Major risk factors for atherosclerotic vascular diseases (e.g., hypertension, smoking, diabetes, and hypercholesterolemia) have been associated with endothelial dysfunction due to increased oxidative stress (11-16). Recent reports have also indicated tha...

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