11-dehydro-thromboxane-b2 and Obesity

Circulating pentraxin 3 (PTX3), the main regulator of the inflammatory response, rapidly increases following cardiovascular events, and low PTX3 is associated with high body mass index.. We conducted a 12-month longitudinal study, to test the hypothesis that laparoscopic adjustable gastric banding (LAGB)-induced weight loss was associated with changes in platelet activation markers and PTX3. Twelve obese patients, scheduled to undergo LAGB, were enrolled at the University Obesity Center. Urinary 11-dehydro-thromboxane (Tx)B2excretion rate was measured on radioimmunoassay, and PTX3 and CD40L were determined on immunoassay. Plasma PTX3 increased by 178.8 and 214.9% (P<0.0001), respectively, 6 and 12 months after LAGB. High-sensitivity CRP decreased by 24 and 29.7% (P<0.0001), whereas CD40L decreased by 64.3 and 58.6% (P=0.002), respectively. Urinary 11-dehydro-TxB2decreased from 1,443 to 715 and 564 pg/mg creatinine, respectively 6 months and 12 months after LAGB (P<0.0001). PTX3 was inversely related to platelet activation markers, 11-dehydro-TxB2and CD40L. Moreover, multiple regression analysis on pooled data showed that plasma PTX3 was an independent predictor of urinary 11-dehydro-TxB2.. There is an association between inflammation, platelet activation and metabolic dysfunction in obesity, and PTX3 is a key player within these circuits.

Topics: Adult; C-Reactive Protein; CD40 Ligand; Female; Follow-Up Studies; Gastric Bypass; Humans; Male; Middle Aged; Obesity; Platelet Activation; Serum Amyloid P-Component; Thromboxane B2

Recent data suggest a decreased clinical efficacy of low-dose aspirin in patients weighing ≥70 kg. We therefore investigated the impact of body weight and class 1 obesity on thromboxane generation and platelet reactivity to arachidonic acid (AA) in 316 patients on dual antiplatelet therapy following angioplasty and stenting.. Platelet surface expression of P-selectin and activated glycoprotein (GP) IIb/IIIa in response to AA were determined by flow cytometry as sensitive markers of platelet activation. Urinary 11-dehydro-thromboxane B2 (11-dehydro-TXB2) and serum TXB2 were measured by commercially-available immunoassays. On-treatment residual AA-inducible platelet aggregation was assessed by light transmission aggregometry (LTA), the VerifyNow aspirin assay and multiple electrode aggregometry (MEA).. Class 1 obesity was independently associated with increased platelet surface expression of P-selectin and activated GPIIb/IIIa, but not with urinary 11-dehydro-TXB2, serum TXB2, and on-treatment platelet aggregation by all assays. Of all measured parameters, only MEA showed a positive albeit very weak correlation with body weight (r = 0.13, p = 0.02). Furthermore, the results of all tests did not differ significantly between patients without and with a body weight ≥ 70 kg. After adjustment for age and diabetes by multivariate logistic regression analysis, the frequency of high-on treatment residual TXB2 generation and high on-treatment residual AA-inducible platelet reactivity (HRTG/HRPR) did not differ significantly between obese and non-obese patients.. Class 1 obesity is associated with enhanced platelet activation in response to AA in patients on dual antiplatelet therapy. This seems to be independent of cyclooxygenase-1 inhibition and does not translate into HRTG/HRPR.

Topics: Aged; Angioplasty; Aspirin; Biomarkers; Blood Platelets; Cardiovascular Diseases; Dual Anti-Platelet Therapy; Female; Flow Cytometry; Humans; Male; Middle Aged; Obesity; P-Selectin; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Platelet Glycoprotein GPIIb-IIIa Complex; Stents; Thromboxane B2; Time Factors; Treatment Outcome

The receptor for advanced glycation end-products (RAGE) has been implicated in obesity-related metabolic disease and accelerated atherothrombosis.. We tested the hypothesis that changes in endogenous secretory (es)RAGE levels as a result of excess adiposity and oxidative stress may contribute to enhancing platelet activation in obese women, thus increasing the cardiovascular risk.. Eighty otherwise healthy obese women and 20 nonobese women were studied.. esRAGE and plasma adiponectin were reduced in obese women [median (interquartile range), 0.18 (0.13-0.26) vs. 0.38 (0.20-0.48) ng/ml, P = 0.003; and 4.4 (2.8-6.4) vs. 10.0 (6.9-12.5) μg/ml, P < 0.0001, respectively] who also displayed higher urinary 11-dehydro-thromboxane B(2) (11-dehydro-TXB(2)) [795 (572-1089) vs. 211 (135-301) pg/mg creatinine; P < 0.0001] and 8-iso-prostaglandin F(2α) (8-iso-PGF(2α)) [544 (402-698) vs. 149 (98-219) pg/mg creatinine; P < 0.0001] compared to nonobese women. Direct correlations between plasma adiponectin and esRAGE (Rho = 0.43; P < 0.0001) and between urinary 8-iso-PGF(2α) and 11-dehydro-TXB(2) (Rho = 0.36; P = 0.001) were observed in obese women. Moreover, plasma esRAGE and urinary 11-dehdro-TXB(2) were inversely related (Rho = -0.29; P = 0.008). On multiple linear regression analysis, urinary 8-iso-PGF(2α) and plasma esRAGE were independent predictors of urinary 11-dehydro-TXB(2). In five obese women, a short-term weight loss program gave a significant increase in esRAGE and decrease in urinary 8-iso-PGF(2α) and 11-dehydro-TXB(2).. In otherwise healthy obese women, low plasma esRAGE levels are associated with reduced circulating adiponectin and enhanced thromboxane biosynthesis, which is in part mediated by increased lipid peroxidation. Thus, excess adiposity may be implicated in RAGE hyperactivation and thromboxane-dependent platelet activation, contributing to obesity-related metabolic and vascular disease.

Topics: Adiponectin; Adult; Anthropometry; Blood Glucose; Blood Pressure; Cardiovascular Diseases; Dinoprost; Female; Humans; Linear Models; Lipid Peroxidation; Lipids; Middle Aged; Obesity; Oxidative Stress; Platelet Activation; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Risk; Thromboxane B2; Weight Loss

Low-grade inflammation may potentially explain the relationship between obstructive sleep apnea syndrome (OSA) and cardiovascular events. However, the respective contribution of intermittent hypoxia and confounders, such as obesity, is still debated.. To monitor urinary leukotriene E(4) (U-LTE(4)), a validated marker of proinflammatory cysteinyl leukotriene production, in OSA; to determine the influence of obesity and other confounders on U-LTE(4) concentrations; to examine the mechanisms involved through transcriptional profiling of the leukotriene pathway in peripheral blood mononuclear cells (PBMCs); and to investigate the effect of continuous positive air pressure (CPAP) on U-LTE(4) concentrations.. We measured U-LTE(4) by liquid chromatography-tandem mass spectrometry.. The U-LTE(4) concentrations were increased (P = .019) in 40 nonobese patients with OSA carefully matched for age, sex, and body mass index (BMI) to 25 control subjects, and correlated (r = 0.0312; P = .017) to the percentage of time spent with mean oxygen saturation (SaO(2)) less than 90%. In a larger cohort of patients with OSA (n = 72), U-LTE(4) increased as a function of BMI (r = 0.445; P = .0002). In those patients, the expression levels of 5-lipoxygenase activating protein mRNA in mononuclear cells exhibited a similar pattern. A stepwise multiple linear regression analysis performed in this cohort identified BMI (P = .001; regression coefficient, 3.33) and percentage of time spent with SaO(2) <90% (P = .001; regression coefficient, 1.01) as independent predictors of U-LTE(4) concentrations. Compared with baseline, CPAP reduced by 22% (P = .006) U-LTE(4) concentrations only in patients with OSA with normal BMI.. Obesity, and to a lesser extent hypoxia severity, are determinant of U-LTE(4) production in patients with OSA.

Topics: 5-Lipoxygenase-Activating Proteins; Adult; Carrier Proteins; Chromatography, Liquid; Female; Humans; Hypoxia; Leukotriene E4; Male; Membrane Proteins; Middle Aged; Obesity; Polysomnography; Prospective Studies; RNA, Messenger; Sleep Apnea, Obstructive; Tandem Mass Spectrometry; Thromboxane B2

Regular exercise is recommended for the non-pharmacological treatment of hypertension, but the mechanisms underlying the lowering of blood pressure remain controversial. Therefore, we studied the effects of 22-week-long training on blood pressure, arterial reactivity, and metabolic abnormalities in a model of genetic obesity and moderate hypertension.. Obese and lean Zucker rats were subjected to treadmill exercise from 8 to 30 weeks of age. Blood pressures were measured by the tail-cuff method, and urine was collected in metabolic cages. At the end of the study, the samples for biochemical determinations were taken, and reactivity of isolated mesenteric and carotid arterial rings was examined in standard organ chambers.. The exercise prevented the elevation of blood pressure which was observed in non-exercised obese Zucker rats, and also reduced blood pressure in the lean rats. The relaxations of norepinephrine-preconstricted mesenteric and carotid arterial rings to acetylcholine and nitroprusside were clearly improved by exercise in the obese rats. In the lean rats exercise enhanced vasorelaxation to nitroprusside in the mesenteric and carotid rings, and to acetylcholine in the carotid preparations. The exercise-induced improvement of endothelium-mediated dilatation to acetylcholine was abolished by nitric oxide synthesis inhibition with NG nitro-L-arginine methyl ester, but not by cyclooxygenase inhibition with diclofenac or functional inhibition of endothelium-dependent hyperpolarization by precontractions with KCl. The urinary excretion of the systemic prostacyclin metabolite (2,3-dinor-6-ketoprostaglandin F1 alpha) was increased two-fold by exercise in the obese and lean rats, whereas that of the thromboxane A2 metabolite (11-dehydrothromboxane B2) remained unaffected. Treadmill training reduced blood glucose, cholesterol, and triglycerides, but did not affect the high levels of insulin in obese Zucker rats.. These results suggest that the antihypertensive effect of long-term exercise in experimental obesity related hypertension is associated with improved vasodilatation. This is expressed as enhanced relaxation via endogenous and exogenous nitric oxide, and increased endothelial prostacyclin production. The improved control of arterial tone after training could be attributed to the alleviation of hyperlipidemia and insulin resistance, whereas hyperinsulinaemia per se remained unaffected.

Topics: 6-Ketoprostaglandin F1 alpha; Acetylcholine; Analysis of Variance; Animals; Blood Glucose; Carotid Arteries; Cholesterol; Cyclooxygenase Inhibitors; Diclofenac; Endothelium, Vascular; Hypertension; In Vitro Techniques; Insulin; Male; Mesenteric Arteries; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitroprusside; Obesity; Physical Exertion; Rats; Rats, Zucker; Thromboxane B2; Triglycerides; Vasodilation; Vasodilator Agents