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...
Background-Reactive oxygen species play a critical role in inducing apoptosis. The small GTPase p21 Ras and the ERK1/2 MAPK have been proposed as key regulators of the signaling cascade triggered by oxidative stress (H 2 O 2 ). Harvey-Ras (Ha-Ras) and Kirsten-Ras (Ki-Ras) isoforms are so far functionally indistinguishable, because they activate the same downstream effectors, including ERK1/2. Moreover, ERK1/2 signaling has been involved in both protection and induction of apoptosis. Methods and Results-Human umbilical vein endothelial cells (HUVECs) were subjected to H 2 O 2 , and apoptosis was detected by fluorescence-activated cell sorting analysis, fluorescence microscopy, and caspase-3 activation. Transfection of Ha-Ras and Ki-Ras genes in HUVECs was performed to evaluate the response to H 2 O 2 . We have found that, whereas Ha-Ras decreases tolerance to oxidative stress, Ki-Ras has a potent antiapoptotic activity. Both effects are mediated by ERK1/2. Tolerance to H 2 O 2 is encoded by a unique stretch of lysines at the COOH terminus of the Ki-Ras, lacking in Ha-Ras, and it is relatively independent of the farnesylated anchor. Inhibition of p21 Ras signaling by farnesylation inhibitors increased the resistance to apoptosis in Ha-Ras-expressing cells. Conclusions-These
OBJECTIVE -To test whether weight loss may improve endothelial dysfunction in human obesity, we recruited 28 healthy obese subjects, aged 30 -46 years, with BMI 30 -43 kg/m 2 .RESEARCH DESIGN AND METHODS -Endothelium-dependent and -independent vasodilation were investigated by intra-arterial infusion of increasing doses of acetylcholine (ACh; 7.5, 15, and 30 g ⅐ ml Ϫ1 ⅐ min Ϫ1 ) and sodium nitroprusside (0.8, 1.6, and 3.2 g ⅐ ml Ϫ1⅐ min Ϫ1 ). Insulin resistance was estimated by homeostasis model assessment (HOMA). Weight loss was obtained by caloric restriction and physical activity.RESULTS -We observed a significant reduction in BMI (from 33.1 Ϯ 4.2 to 27.5 Ϯ 4.5 kg/m 2 , Ϫ16.9%, P Ͻ 0.0001) and in waist circumference (from 108.2 Ϯ 12.1 to 96.8 Ϯ 12.9 cm, Ϫ10.5%, P Ͻ 0.0001). Weight loss was also associated with a significant increase in AChstimulated forearm blood flow (FBF), from 7.4 Ϯ 2.8 to 12.9 Ϯ 3.4 ml ⅐ 100 ml Ϫ1 of tissue ⅐ min Ϫ1 kg/m 2 (P Ͻ 0.0001). Multivariate regression analysis demonstrated that the only independent predictor of FBF was HOMA, accounting for 44.5% of the variation, whereas the addition of BMI explained another 2.3% of the variation.CONCLUSIONS -Our data demonstrate that energy-restricted diet associated with physical activity induce a significant and clinically relevant improvement in ACh-stimulated vasodilation in obese healthy subjects. Diabetes Care 26:1673-1678, 2003W e recently reported that obesity and abdominal fat distribution are inversely related to endothelium-dependent vasodilation. We have also demonstrated that indexes of insulin sensitivity, which are linearly related to BMI and waist-to-hip ratio (WHR), predict the depressed acetylcholine (ACh)-stimulated forearm blood flow (FBF) in obese subjects (1). These findings are of considerable clinical importance because endothelial dysfunction is considered the early manifestation of the atherosclerotic process (2-4). Impaired endotheliumdependent vasodilation, caused by insulin resistance (IR), may be the mechanism by which obesity confers increased risk for cardiovascular morbidity and mortality. In fact, IR represents a major underlying abnormality driving coronary and extracoronary atherosclerosis and cardiovascular diseases, which are the principal worldwide causes of morbidity and mortality (5). Our previous observations (1) led us to hypothesize that weight loss might be useful in both improving endothelial dysfunction and reducing the risk of subsequent cardiovascular events. This hypothesis is also supported by recent evidence showing that both coronary (6,7) and forearm (8) endothelial dysfunction predict long-term atherosclerotic disease progression and cardiovascular event rates. Endothelial dysfunction associated with obesity is a very important medical problem in light of the evidence that the prevalence of obesity has significantly increased over the last few decades in developed and developing countries (9,10), becoming a major global public health problem (10). Many adverse clinical features associated wi...
BackgroundA close relationship between Metabolic Syndrome (MetS) and Chronic Obstructive Pulmonary Disease (COPD) has been described, but the exact nature of this link remains unclear. Current epidemiological data refer exclusively to the MetS prevalence among patients with COPD and data about the prevalence of COPD in MetS patients are still unavailable.Aim of the studyTo analyse and compare risk factors, clinical and metabolic characteristics, as well as the main respiratory function parameters, among patients affected by MetS, COPD or both diseases.PatientsWe recruited 59 outpatients with MetS and 76 outpatients with COPD. After medical history collection, physical examination, blood sampling for routine analysis, spirometric evaluation, they were subdivided into MetS (n = 46), MetS+COPD (n = 60), COPD (n = 29).ResultsA MetS diagnosis was assigned to 62% of COPD patients recruited in the COPD Outpatients Clinic of the Pneumology Department, while the COPD prevalence in MetS patients enrolled in the Internal Medicine Metabolic Disorders Outpatients Clinic was 22%. More than 60% of subjects enrolled in each Department were unaware that they suffered from an additional disease. MetS+COPD patients exhibited significantly higher C-peptide levels. We also found a positive relation between C-peptide and pack-years in all subjects and a negative correlation between C-peptide and vitamin D only in current smokers. Finally, a negative association emerged between smoking and vitamin D.ConclusionsWe have estimated, for the first time, the COPD prevalence in MetS and suggest a potential role of smoking in inducing insulin resistance. Moreover, a direct effect of smoking on vitamin D levels is proposed as a novel mechanism, which may account for both insulin resistance and COPD development.
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