Basal Endothelial Nitric Oxide Release is Preserved in Overweight and Obese Adults

OBJECTIVE: Impaired basal nitric oxide release is associated with a number of cardiovascular disorders including hypertension, arterial spasm, and myocardial infarction. We determined whether basal endothelial nitric oxide release is reduced in otherwise healthy overweight and obese adult humans.RESEARCH METHODS AND PROCEDURES: Seventy sedentary adults were studied: 32 normal weight (BMI/m(2)), 24 overweight (BMI \u3e or = 25 \u3c 30 kg/m(2)), and 14 obese (BMI \u3e or = 30 kg/m(2)). Forearm blood flow (FBF) responses to intra-arterial infusions of N(g)-monomethyl-L-arginine (5 mg/min), a nitric oxide synthase inhibitor, were used as an index of basal nitric oxide release.RESULTS: N(g)-monomethyl-L-arginine elicited significant reductions in FBF in the normal weight (from 4.1 +/- 0.2 to 2.7 +/- 0.2 mL/100 mL tissue/min), overweight (4.1 +/- 0.1 to 2.8 +/- 0.2 mL/100 mL tissue/min), and obese (3.9 +/- 0.3 to 2.7 +/- 0.2 mL/100 mL tissue/min) subjects. Importantly, the magnitude of reduction in FBF (approximately 30%) was similar among the groups.DISCUSSION: These results indicate that the capacity of the endothelium to release nitric oxide under basal conditions is not compromised in overweight and obese adults

Gender Differences in Endothelial Tissue-type Plasminogen Activator Release in Middle-aged Adults.

Between the ages of 45 and 65 years, the incidence of myocardial infarction is three times higher in men compared with women. In addition, the prevalence of thrombotic stroke is ∼50% greater in men than women (1). The mechanisms behind this gender difference in atherothrombotic events remain unclear. Impaired endothelial regulation of fibrinolysis, specifically reduced capacity to release tissue-type plasminogen activator (t-PA), has been linked directly to increased atheromatous plaque burden and increased coronary atherothrombosis (2,3). Endothelial t-PA release is the predominant physiologic mechanism governing endogenous fibrinolysis. Currently, it is unknown if a gender difference in endothelial t-PA release exists. If so, this may contribute to the gender-related disparity in the prevalence and incidence of atherothrombotic events in middle-aged adults. We tested the hypothesis that the capacity of the endothelium to release t-PA is greater in middle-aged women compared with men

Impaired Endothelium-dependent Vasodilation in Normotensive and Normoglycemic Obese Adult Humans

Acetylcholine (ACh)-mediated endothelium-dependent vasodilation has been shown to be impaired in obese adults. However, the mechanisms responsible for this impairment are not clear. We determined whether the blunted forearm vasodilator response to acetylcholine with obesity is due, at least in part, to reduced muscarinic receptor responsiveness. Twenty-eight sedentary middle-aged adults were studied: 14 normal weight (BMI, 23.6 +/- 0.5 kg/m) and 14 obese (32.2 +/- 0.9 kg/m). Forearm blood flow (FBF) was determined in response to intraarterial infusion of acetylcholine (8-128 microg/min) and sodium nitroprusside (SNP: 2.0-8.0 microg/min). Regardless of the dose, forearm blood flow responses to acetylcholine were 25% (P \u3c 0.01) lower in the obese (from 4.2 +/- 0.3 to 12.0 +/- 0.8 mL/100 mL tissue/min) compared with normal weight (4.4 +/- 0.3 to 16.9 +/- 1.0 mL/100 mL tissue/min) adults. Of note, forearm blood flow responses to acetylcholine plateaued at doses higher than 32 microg/min in both groups, no further increase in forearm blood flow was observed at either 64 or 128 microg/min. EC50 for acetylcholine-stimulated vasodilation was not different between the obese (7.8 +/- 0.8 microg/min) and normal weight (7.8 +/- 0.6 microg/min) adults. There were no group differences in the vasodilator response to sodium nitroprusside. These results indicate that the obesity-related impairment in acetylcholine-mediated vasodilation in the human forearm is not due to reduced muscarinic receptor responsiveness or sensitivity

Metabolic Syndrome and Endothelial Fibrinolytic Capacity in Obese Adults

The metabolic syndrome (MetS) often accompanies obesity and contributes to the increased risk of atherothrombotic events with increased body fatness. Indeed, the risks for coronary artery disease and acute vascular events are greater with obesity combined with MetS compared with obesity alone. Endothelial release of tissue-type plasminogen activator (t-PA) is a key defense mechanism against thrombosis and has been shown to be impaired with obesity. The aim of the present study was to determine whether the presence of MetS exacerbates endothelial fibrinolytic dysfunction in obese adults. Net endothelial release of t-PA was determined in vivo in response to intrabrachial infusions of bradykinin and sodium nitroprusside in 47 sedentary adults: 15 normal weight (age 57 +/- 2 yr; body mass index 22.9 +/- 0.5 kg/m(2)), 14 obese but otherwise healthy (55 +/- 1 yr; 29.4 +/- 0.3 kg/m(2)), and 18 obese with MetS (55 +/- 2 yr; 32.3 +/- 1 kg/m(2)). MetS was established according to National Cholesterol Education Program ATP III criteria. Net release of t-PA antigen to bradykinin was approximately 50% lower (P \u3c 0.01) in the obese (from 2.5 +/- 1.9 to 37.1 +/- 5.3 ng.100 ml tissue(-1).min(-1)) and obese with MetS (from 0.4 +/- 0.8 to 32.5 +/- 3.8 ng.100 ml tissue(-1).min(-1)) compared with normal-weight (from 0.9 +/- 1.0 to 74.3 +/- 8.1 ng.100 ml tissue(-1).min(-1)) subjects. However, there were no significant differences in the capacity of the endothelium to release t-PA in the obese and obese with MetS adults. These results indicate that the presence of the MetS does not worsen the obesity-related endothelial fibrinolytic dysfunction

Influence of Metabolic Syndrome on Biomarkers of Oxidative Stress and Inflammation in Obese Adults

OBJECTIVE: Both obesity and the metabolic syndrome (MetS) have been independently linked with increased oxidative and inflammatory stress. This study tested the hypothesis that obesity with MetS is associated with greater oxidative and inflammatory burden compared with obesity alone.RESEARCH METHODS AND PROCEDURES: Forty-eight normal-weight and 40 obese (20 without MetS; 20 with MetS) adults were studied. MetS was defined according to National Cholesterol Education Program Adult Treatment Panel III criteria. Plasma concentrations of oxidized low-density lipoprotein, C-reactive protein, tumor necrosis factor-alpha, interleukin (IL)-6, and IL-18 were determined by enzyme immunoassay.RESULTS: Plasma biomarkers of oxidative stress and inflammation were lowest in normal-weight controls. Of note, obese MetS adults demonstrated significantly higher plasma concentrations of oxidized low-density lipoprotein (62.3 +/- 3.2 vs. 54.0 +/- 4.0 U/L; p \u3c 0.05), C-reactive protein (3.0 +/- 0.6 vs. 1.5 +/- 0.3 mg/L; p \u3c 0.01), tumor necrosis factor-alpha (2.1 +/- 0.1 vs. 1.6 +/- 0.1 pg/mL; p \u3c 0.05), IL-6 (2.8 +/- 0.4 vs. 1.4 +/- 0.2 pg/mL; p \u3c 0.01), and IL-18 (253 +/- 16 vs. 199 +/- 16 pg/mL; p \u3c 0.01), compared with obese adults without MetS.DISCUSSION: These results suggest that MetS heightens oxidative stress and inflammatory burden in obese adults. Increased oxidative and inflammatory stress may contribute to the greater risk of coronary heart disease and cerebrovascular disease in obese adults with MetS

Aging, Exercise, and Endothelial Progenitor Cell Clonogenic and Migratory Capacity in Men

Numerical and functional impairment of circulating endothelial progenitor cells (EPCs) is thought to contribute to vascular aging and the associated increase in cardiovascular risk. We tested the following hypotheses: 1) EPC clonogenic and migratory capacity decrease progressively with age in healthy, sedentary adult men; and 2) regular aerobic exercise will improve EPC clonogenic and migratory capacity in previously sedentary middle-aged and older men. Peripheral blood samples were collected from 46 healthy sedentary men: 10 young (26 +/- 1 yr), 15 middle-aged (47 +/- 1 yr), and 21 older (63 +/- 1 yr). Mononuclear cells were isolated and preplated for 2 days, and nonadherent cells were further cultured for 7 days to determine EPC colony-forming units. Migratory activity of EPCs was determined using a modified Boyden chamber. Ten sedentary middle-aged and older men (59 +/- 3 yr) were studied before and after a 3-mo aerobic exercise intervention. The number of EPC colony-forming units was approximately 75% lower (P \u3c 0.01) in middle-aged (12 +/- 3) and older (8 +/- 2) compared with young (40 +/- 7) men. There was no difference in colony count between middle-aged and older men. EPC migration (fluorescent units) was significantly reduced in older (453 +/- 72) compared with young (813 +/- 114) and middle-aged (760 +/- 114) men. The exercise intervention increased (P \u3c 0.05) both EPC colony-forming units (10 +/- 3 to 22 +/- 5) and migratory activity (683 +/- 96 to 1,022 +/- 123) in previously sedentary middle-aged and older men. These results provide further evidence that aging adversely affects EPC function. Regular aerobic-endurance exercise, however, is an effective lifestyle intervention strategy for improving EPC clonogenic and migratory capacity in middle-aged and older healthy men