thromboxane-b2 and Atherosclerosis

Topics: Adenosine Diphosphate; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Atherosclerosis; Biomarkers; Biotransformation; Blood Coagulation Tests; Blood Platelets; Cardiovascular Diseases; Clopidogrel; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Drug Interactions; Drug Resistance; Hemorrhage; Humans; Platelet Activation; Platelet Aggregation Inhibitors; Platelet Function Tests; Prospective Studies; Randomized Controlled Trials as Topic; Receptors, Purinergic P2; Receptors, Purinergic P2Y1; Receptors, Purinergic P2Y12; Thrombosis; Thromboxane A2; Thromboxane B2; Ticlopidine; Treatment Failure

Aspirin is the mainstay antiplatelet treatment in patients with high risk of cardiovascular atherothrombotic events, and its beneficial effect is documented in several clinical trials. Nevertheless, the effectiveness of aspirin has been questioned by the emergence of the concept of 'aspirin resistance' (AR). This phenomenon, although lacking a precise definition, covers the fact that some patients do not exhibit the expected platelet inhibition by use of various techniques for measuring platelet function. In this critical review, we evaluate the methods used for measuring AR. We will discuss the available data regarding the prevalence and the clinical importance of the phenomenon. Finally, the potential mechanisms underlying AR are considered.

Topics: Aspirin; Atherosclerosis; Cardiovascular Diseases; Drug Resistance; Humans; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Thrombosis; Thromboxane A2; Thromboxane B2

To test the hypothesis that selective inhibition of cyclooxygenase (COX)-2 would result in exercise-induced platelet activation by causing a shift in the endogenous thromboxane (TX)/prostacyclin balance, a double blind, randomized study comparing aspirin (300 mg/d) with rofecoxib (25 mg/d) (cross-over design, 14 days washout between treatments) in n = 10 trained healthy volunteers was carried out. Physical exercise resulted only in a minor platelet activation, as reflected by the expression of basal or ADP-stimulated platelet activation markers or basal plasma concentrations of TXB(2). Aspirin significantly reduced TXB(2) in plasma while rofecoxib significantly increased TXB(2) in urine. Although no increase in systemic prostacyclin concentration was observed, there was a significant exercise-related increase in both platelet cAMP and cGMP without any drug-related effects. It is concluded that, in trained healthy volunteers, selective inhibition of COX-1 (aspirin) or COX-2 (rofecoxib) does not affect systemic prostacyclin synthesis after physical exercise. However, our data do not exclude the possibility that in subjects at risk for atherothrombotic complications (e.g. patients with advanced atherosclerotic disease) COX-2 inhibitors may result in platelet activation by inhibiting endothelial prostacyclin formation.

Topics: Adenosine Diphosphate; Adult; Aspirin; Atherosclerosis; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Double-Blind Method; Endothelium; Epoprostenol; Exercise; Humans; Isoenzymes; Lactones; Male; Platelet Activation; Rest; Risk Factors; Sulfones; Thrombosis; Thromboxane B2

Cyclooxygenase-derived thromboxane (TxA2) and prostacyclin (PGI2) regulate atherogenesis in preclinical models. However, the relationship between TxA2 and PGI2 biosynthesis, vascular inflammation, and atherosclerotic cardiovascular disease (ASCVD) progression in humans remains unclear. The association between stable urine metabolites of thromboxane (TxA2-M) and prostacyclin (PGI2-M), circulating levels of cellular adhesion molecules (CAMs: E-selectin, P-selectin), chemokines and C-reactive protein, and the incidence of major adverse cardiovascular events (MACE) were evaluated in 120 patients with stable ASCVD on aspirin therapy. Urinary TxA2-M levels were significantly correlated with circulating P-selectin (r=0.319, p<0.001) and E-selectin (r=0.245, p=0.007) levels, and associated with higher risk of MACE (p=0.043). In contrast, PGI2-M levels were not significantly associated with CAM levels or MACE. These results provide insight into the contribution of TxA2 biosynthesis to ASCVD progression in humans, and suggest that patients with elevated TxA2-M levels may be predisposed to advanced platelet and endothelial activation and higher risk of adverse cardiovascular outcomes.

Topics: Atherosclerosis; Endpoint Determination; Female; Humans; Inflammation; Male; Middle Aged; Prognosis; Thromboxane B2

Optimal vascular function is a hallmark of cardiovascular health. Specifically, the balance of vasoconstricting and vasodilating substances is recognized as a marker of vascular health. One of the greatest challenges to vascular health and vasodilatory balance is tumor necrosis factor alpha (TNFα)-mediated inflammation. Uncovering effective strategies that maintain a vascular environment that is more vasodilatory and antithrombotic in the face of an inflammatory challenge is favorable.. To test the ability of various antithrombotic and provasodilatory treatments, as well as combinations thereof, to prevent unfavorable changes in markers of endothelial dysfunction in human umbilical vein endothelial cells when presented with an inflammatory challenge.. Human umbilical vein endothelial cells were pretreated with exercise-like levels of laminar shear stress (LSS), aspirin, celecoxib, and their combination before a TNFα challenge. Western blot analysis as well as colorimetric assays were used to determine levels of endothelial nitric oxide synthase (eNOS) and prostacyclin (6-keto PGF1α)/thromboxane (TXB2) metabolite ratio, respectively.. Neither aspirin nor celecoxib were effective in preventing TNFα-induced reduction in eNOS. Further, aspirin was unable to maintain baseline levels of prostacyclin/thromboxane ratio in the face of the inflammatory challenge. Laminar shear stress, aspirin/LSS combination, and celecoxib/LSS combination were all able to prevent TNFα-induced alterations in eNOS levels and prostacyclin/thromboxane ratio.. Effective strategies to maintain a healthy endothelium, and therefore resistance vessel health, need to include exercise-levels of shear stress to be effective.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Atherosclerosis; Celecoxib; Cells, Cultured; Epoprostenol; Exercise; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Nitric Oxide Synthase Type III; Stress, Mechanical; Thromboxane B2; Tumor Necrosis Factor-alpha

Chronic inflammation plays a major role in the formation and progression of atherosclerotic plaques. To clarify the mode of action of aged garlic extract (AGE) to retard atherosclerosis, we investigated whether AGE suppresses the inflammation in apolipoprotein E-knockout (ApoE-KO) mice.. ApoE-KO mice were fed standard diet with or without 3% AGE for 12 wk. AGE feeding inhibited the progression of atherosclerotic lesion by 27% and reduced the level of C-reactive protein (CRP) and thromboxane B. The anti-atherosclerotic effect of AGE involves the suppression of inflammation by reducing the serum level of CRP and TXB

Topics: AMP-Activated Protein Kinases; Animals; Atherosclerosis; Biomarkers; C-Reactive Protein; Diet; Disease Progression; Garlic; Inflammation; Interleukin-1 Receptor-Associated Kinases; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout, ApoE; Plant Extracts; Thromboxane B2; Tumor Necrosis Factor-alpha

Cushing Syndrome (CS) is implicated by increased cardiovascular risk (CVR) leading to increased morbidity and mortality. Oxidative stress (OS) and platelet activation (PA) are associated with increased CVR. However, scarce data of OS in CS exist. Our objective was to determine the oxidant-antioxidant balance in CS.. Fourteen patients with CS at diagnosis and fourteen healthy subjects (NS) were evaluated OS by measuring plasma 15-F2t -Isoprostane (15-F2t -IsoP), PA by thromboxaneB2 levels (TXB2 ), and antioxidant reserve measuring total antioxidant capacity (TAC) and serum vitamin E.. 15-F2t -IsoP and TXB2 levels were significantly higher (P < 0·01) in CS, while vitamin E levels were higher in NS (P < 0·03). 15-F2t -IsoP levels were significantly higher (P < 0·01) in complicated vs not-complicated CS and NS and significantly higher (P < 0·03) in CS not-complicated vs NS. TXB2 levels were significantly reduced (P < 0·03) in NS vs complicated and not-complicated CS. A negative correlation between Vitamin E and UFC was observed in CS (P < 0·05 r = -0·497). TXB2 correlated with glucose, HbA1c and T-score (P < 0·05 r = 0·512, P < 0·03 r = 0·527 and P < 0·01 r = 0·783, respectively) and HDL (P < 0·01 r = -0·651). 15-F2t -IsoP correlated with triglicerides, HbA1c and diastolic pressure (P < 0·01 r = 0·650, P < 0·03 r = 0·571 and P < 0·05 r = 0·498, respectively) and HDL (P < 0·03 r = -0·594).. This study emphasizes the major role of OS in CS. As our findings demonstrated that enhanced OS and PA take place in this rare metabolic disorder which is associated with increased CVR, it could be suggested that these biochemical alterations can further contribute in the pathogenesis of atherosclerosis, increased CVR and mortality in CS.

Topics: Adult; Anthropometry; Antioxidants; Atherosclerosis; Cardiovascular Diseases; Cushing Syndrome; Female; Glucose; Hormones; Humans; Isoprostanes; Male; Middle Aged; Oxidants; Oxidative Stress; Platelet Activation; Thromboxane B2; Vitamin E

Fish oil supplementation (FOS) is known to have cardiovascular benefits. However, the effects of FOS on thrombosis are incompletely understood. We sought to determine if the use of FOS is associated with lower indices of atherothrombotic risk in patients with suspected coronary artery disease (sCAD). This is a subgroup analysis of consecutive patients with sCAD (n=600) enrolled in the Multi-Analyte, Thrombogenic, and Genetic Markers of Atherosclerosis study. Patients on FOS were compared with patients not on FOS. Lipid profile was determined by vertical density gradient ultracentrifugation (n=520), eicosapentaenoic acid+docosahexaenoic acid was measured by gas chromatography (n=437), and AtherOx testing was performed by immunoassay (n=343). Thromboelastography (n=419), ADP- and collagen-induced platelet aggregation (n=137), and urinary 11-dehydrothromboxane B2 levels (n=259) were performed immediately before elective coronary angiography. In the total population, FOS was associated with higher eicosapentaenoic acid+docosahexaenoic acid content (p<0.001), lower triglycerides (p=0.04), total very low-density lipoprotein cholesterol (p=0.002), intermediate-density lipoprotein cholesterol (p=0.02), and AtherOx levels (p=0.02) but not in patients on lipid-lowering therapy. Patients not on lipid-lowering therapy taking FOS had lower very low-density lipoprotein cholesterol, intermediate-density lipoprotein cholesterol, remnant lipoproteins, triglycerides, low-density lipoprotein cholesterol, AtherOx levels, collagen-induced platelet aggregation, thrombin-induced platelet-fibrin clot strength, and shear elasticity (p<0.03 for all). In clopidogrel-treated patients, there was no difference in ADP-induced aggregation between FOS groups. Patients on FOS had lower urinary 11-dehydrothromboxane B2 levels regardless of lipid-lowering therapy (p<0.04). In conclusion, the findings of this study support the potential benefit of FOS for atherothrombotic risk reduction in sCAD with the greatest benefit in patients not receiving lipid-lowering therapy. Future prospective studies to compare FOS with lipid-lowering therapy and to assess the independent effects of FOS on thrombogenicity are needed.

Topics: Aged; Atherosclerosis; Biomarkers; Cholesterol; Coronary Artery Disease; Dietary Supplements; Docosahexaenoic Acids; Eicosapentaenoic Acid; Female; Fish Oils; Humans; Lipoproteins; Male; Middle Aged; Risk Factors; Thrombelastography; Thrombosis; Thromboxane B2; Triglycerides

Yindan Xinnaotong capsule has been used for treating cardio-cerebrovascular diseases for several decades in China. Exercise training can protect against the development of atherosclerosis. The aim of the present study is to evaluate the joint effect of YXC and exercise on atherosclerosis in rats.. A combined method involving low shear stress and a high-fat diet was used to establish the atherosclerosis model in rats. Partial ligation of the left common carotid artery was performed, and then the rats were divided into 9 treatment groups according to a 3 × 3 factorial design with two factors and three levels for each factor, swimming of 0, 0.5, 1 h daily and YXC administration of 0, 1, 2 g/kg p.o. daily. Next the interventions of swimming and YXC were executed for 8 weeks. After that, blood samples were collected to determine blood viscosity, plasma viscosity, haematocrit (HCT), fibrinogen (FIB), blood lipid profile (including total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), triglyceride (TG) and high-density lipoprotein-cholesterol (HDL-C)), nitric oxide (NO), 6-keto- prostaglandin (PG) F1α, endothelin (ET) and thromboxane (TX) B2. The common carotid arteries of the rats were harvested to examine pathological changes, wall thickness and circumference, and the expression of SM22αwas assayed via immune-histochemistry.. The early pathological changes were observed. The joint effects of YXC and swimming showed significant changes in the examined parameters: (1) decreases in plasma viscosity, blood viscosity and FIB; (2) increases in NO and 6-keto-PGF1α; (3) decreases in ET and TXB2; and (4) decreases in LDL-C and TG. The combination of 2 g/kg YXC and 1 h of swimming led to synergistic decreases in LDL-C and TG. The interactive effect between YXC and swimming was obvious in decreasing wall thickness. Swimming alone was able to up-regulate the expression of SM22α.. In conclusion, this study indicates that the combination of YXC and swimming may prevent atherosclerosis through a synergistic effect between YXC and swimming in improving blood circulation, hemorheological parameters, blood lipids levels and the vascular endothelium in rats. The vascular remodeling may be contributed to the prevention effects on AS by up-regulating SM22α.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Atherosclerosis; Blood Circulation; Capsules; China; Cholesterol; Diet, High-Fat; Drugs, Chinese Herbal; Endothelium, Vascular; Fibrinogen; Lipids; Male; Microfilament Proteins; Muscle Proteins; Nitric Oxide; Physical Conditioning, Animal; Phytotherapy; Rats, Sprague-Dawley; Swimming; Thromboxane B2; Triglycerides

Atherosclerosis (AS) can result in severe cardiovascular diseases. Early indications of AS include disorders in lipid metabolism, inflammatory responses, and endothelial dysfunction. Statins are the preferred drugs for stabilizing atherosclerotic plaques because of their lipid-lowering, anti-inflammation and endothelial-protection activities. However, they can exhibit side effects and are effective in only one-third of patients. Many natural products (especially traditional Chinese medicines (TCMs)) possessing similar lipid-lowering, anti-inflammation and antioxidant activities are of interest in many studies exploring new AS drug therapy. The widely distributed hawthorn is used to prevent and cure heart disease not only in China but also in the United States and several European countries. For example, the fruit of Crataegus pinnatifida Bge. and Crataegus pinnatifida Bge. var. major N.E.Br. (a commonly used hawthorn fruit in China) is used in combination with other TCMs to treat AS. Studies have also shown that the water extracts of these two hawthorn fruits are effective against hyperlipidemia by lowering lipid levels, reducing endothelial dysfunction, and inhibiting inflammation. The aim of the study is to investigate the effect and possible mechanisms of the aqueous extract of Crataegus pinnatifida var. major on AS rats.. The fruit of Crataegus pinnatifida var. major was extracted with 70% ethanol; the ethanol extract was chromatographed on a D101 macroporous resin to obtain a sugar-free aqueous extract (AECP). Atherosclerotic rats were fed a high-fat diet and injected with vitamin D3 and ovalbumin. Rats were divided into five groups: normal, model, model plus simvastatin, model plus low-dose AECP, and model plus high-dose AECP. AECP and simvastatin were administered (via the intragastric route) to AECP groups and the simvastatin group. For normal and model groups, water was given for 4 weeks. After 12 weeks, levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C) and high-density lipoprotein-cholesterol (HDL-C) in blood were measured by an automatic biochemistry analyzer. Serum concentrations of interleukin (IL)-1β, IL-8, nitric oxide (NO), endothelin (ET), 6-keto-prostaglandin F1α (6-keto-PGF1α) and thromboxane B2 (TXB2) were determined by radioimmunoassay (RIA). Serum concentrations of C-reactive protein (CRP) and IL-18 were measured by enzyme-linked immunosorbent assay (ELISA). Pathological changes in arteries were observed using an optical microscope and the intima-media thickness (IMT) calculated. Cholesterol deposition was evaluated by filipin staining. Chemical ingredients in AECP were analyzed by qualitative and quantitative means by high-performance liquid chromatography (HPLC).. AECP significantly reduced the levels of TC, TG and LDL-C but increased HDL-C levels. It also decreased the concentrations of CRP, IL-1β, IL-8 and IL-18. AECP increased levels of ET and TXB2 but increased 6-keto-PGF1α levels. Histopathological examination showed that AECP inhibited pathological changes in the arteries of AS rats and reduced IMT. Chemical analysis suggested that the main components of AECP were chlorogenic acid, procyanidin B2, (-)-epicatechin, rutin and isoquercitrin.. These data suggest that AECP can inhibit AS progression in high-fat-diet-fed rats. Possible mechanisms of action include improvement of lipid metabolism, decrease in inflammatory cytokine responses, and protection of the endothelium.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Atherosclerosis; Biflavonoids; C-Reactive Protein; Catechin; Chlorogenic Acid; Crataegus; Diet, High-Fat; Drugs, Chinese Herbal; Endothelins; Fruit; Interleukins; Lipids; Male; Nitric Oxide; Plant Extracts; Proanthocyanidins; Quercetin; Random Allocation; Rats; Rats, Wistar; Rutin; Thromboxane B2; Water

Intermittent hypoxia, the main stimulus of obstructive sleep apnoea (OSA), induces inflammation, leading to early atherosclerosis. Whether the cyclooxygenase (COX) pathway contributes to intermittent hypoxia-induced atherosclerosis remains to be determined. We studied the effects of 8-weeks of intermittent hypoxia exposure on COX-pathway gene expression and atherosclerosis, and the influence of COX-1 inhibition by SC-560 on atherosclerosis progression in aortas of apolipoprotein E(-/-) mice. Urinary 11-dehydrothromboxane B2 (11-dTXB2) was assessed in 50 OSA subjects free of cardiovascular risk factor matched for age and body mass index with 25 controls, and 56 OSA with cardiovascular risk factor. Intermittent hypoxia significantly increased atherosclerotic lesion sizes, mRNA levels of COX-1 and thromboxane synthase (TXBS). Lesion sizes correlated to COX-1 (r = 0.654, p = 0.0003) and TXBS (r = 0.693, p<0.0001) mRNA levels. COX-1 inhibition reduced lesion progression in intermittent hypoxia mice only (p = 0.04). Urinary 11-dTXB2 was similar in OSA subjects free of cardiovascular risk factor and controls, but was increased by 13% (p = 0.007) in OSA subjects with cardiovascular risk factor compared with those without. Although OSA itself was not associated with increased urinary 11-dTXB2 concentration, the COX-1 pathway was activated in intermittent hypoxia-exposed mice and in OSA subjects presenting with cardiovascular risk factor, and may contribute to intermittent hypoxia-induced atherogenesis. COX-1 inhibition could be of clinical interest in the prevention of cardiovascular morbidity in OSA.

Topics: Adult; Animals; Aorta; Apolipoproteins E; Atherosclerosis; Body Mass Index; Body Weight; Case-Control Studies; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Female; Gene Expression Regulation, Enzymologic; Hematocrit; Humans; Hypoxia; Male; Mice; Mice, Transgenic; Middle Aged; Pyrazoles; Risk Factors; Sleep Apnea, Obstructive; Thromboxane B2

Previous studies have demonstrated that statin can reduce the risk of acute coronary syndrome. In order to explore the mechanism, we observed the effects of pravastatin on plaque stability in atherosclerotic rabbits. Sixteen male rabbits were fed with a high fat diet following their damaged abdominal aortic endothelium by using catheter. Eight of them were administered with pravastatin (10 mg·kg(-1)·d(-1)) for 4 weeks. Then the rabbit atherosclerotic plaque rupture and thrombosis were triggered by injection of viper venom and histamine. Compared with model group, the thrombus area on aorta in pravastatin-treated group was reduced. Fibre cap on plaque was more thick and integrant, and inflammatory cell infiltration was also decreased. Serum total cholesterol, triglyceride, low density lipoprotein-cholesterol and contents of cholesterol in abdominal aorta were decreased. 6-Keto-prostaglandin F(1α) (6-keto-PGF(1α)) level and ratio of 6-keto-PGF(1α)/thromboxane B(2) (TXB(2)) in aorta were significantly increased. These results suggested that pravastatin could increase plaque stability and inhibit thrombosis through both lipid-dependent and lipid-independent way.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anticholesteremic Agents; Aorta; Aorta, Abdominal; Atherosclerosis; Cholesterol; Cholesterol, LDL; Diet, High-Fat; Disease Models, Animal; Histamine; Hyperlipidemias; Male; Plaque, Atherosclerotic; Pravastatin; Rabbits; Thrombosis; Thromboxane B2; Triglycerides; Viper Venoms

Atherosclerosis is the principal cause of mortality in industrialized countries. Its development is influenced by several mediators of which thromboxane A(2) (TXA(2)) and 8-iso-PGF(2α) have recently received a lot of attention. This study aimed to investigate the effect of a dual thromboxane synthase inhibitor and thromboxane receptor antagonist (BM-573) and ASA on lesion formation in apolipoprotein E-deficient mice. The combination of ASA and BM-573 was also studied. Plasma measurements demonstrated that the treatments did not affect body weight or plasma cholesterol levels. BM-573, but not ASA, significantly decreased atherogenic lesions as demonstrated by macroscopic analysis. Both treatments alone inhibited TXB(2) synthesis but only BM-573 and the combination therapy were able to decrease firstly, plasma levels of soluble intracellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) and secondly, the expression of these proteins in the aortic root of Apo E. These results were confirmed in endothelial cell cultures derived from human saphenous vein endothelial cells (HSVECs). In these cells, BM-573 also prevented the increased mRNA expression of ICAM-1 and VCAM-1 induced by U-46619 and 8-iso-PGF(2α). Our results show that a molecule combining receptor antagonism and thromboxane synthase inhibition is more efficient in delaying atherosclerosis in Apo E(-/-) mice than sole inhibition of TXA(2) formation.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Apolipoproteins E; Aspirin; Atherosclerosis; Dinoprost; Drug Therapy, Combination; Endothelial Cells; Humans; Intercellular Adhesion Molecule-1; Mice; Mice, Knockout; Receptors, Thromboxane; Saphenous Vein; Sulfonylurea Compounds; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase; Vascular Cell Adhesion Molecule-1

Postmortem studies have demonstrated that morbidly obese subjects, surprisingly, have less coronary atherosclerosis than obese subjects. However, the reasons for this apparent protection from atherosclerosis are not yet clear. Thromboxane A2, a marker of platelet activation, is greater in obese subjects than in lean subjects, and this might be a clue to their increased cardiovascular risk. However, data on thromboxane A2 in morbidly obese subjects are lacking; therefore, we hypothesized that lower levels of thromboxane A2 in morbidly obese subjects might play a role in their lower atherothrombotic burden. We measured the serum levels of thromboxane B2 (TxB2), a stable metabolite of thromboxane A2, high-sensitivity C-reactive protein (hs-CRP) and leptin in 17 lean subjects (body mass index [BMI] 22.9 ± 1.6 kg/m(2)), 25 obese subjects (BMI 32.6 ± 2.4 kg/m(2)), and 23 morbidly obese subjects (BMI 48.6 ± 7.1 kg/m(2)), without insulin resistance, diabetes, or overt cardiovascular disease. The serum TxB2 levels were lower in the lean subjects than in the obese subjects (p = 0.046) and in the morbidly obese subjects than in the lean and obese subjects (p = 0.015 and p <0.001, respectively). In contrast, the hs-CRP and leptin levels were greater in the obese than in the lean subjects (hs-CRP, p <0.001; leptin, p <0.001) and in the morbidly obese subjects than in the lean subjects (p <0.001 for both). Leptin was also higher in the morbidly obese subjects than in the obese subjects (p <0.001). TxB2 negatively correlated with leptin and BMI. hs-CRP correlated with leptin, and both also correlated with waist circumference, BMI, and homeostasis model assessment of insulin-resistance. In conclusion, insulin-sensitive morbidly obese subjects had lower levels of TxB2 than the obese subjects and lean subjects, suggesting that reduced platelet activation could play a role in the paradoxical protection of morbidly obese subjects from atherosclerosis, despite the greater levels of leptin.

Topics: Adult; Atherosclerosis; Body Mass Index; C-Reactive Protein; Female; Humans; Leptin; Male; Middle Aged; Obesity, Morbid; Thromboxane A2; Thromboxane B2

Several murine models are susceptible to atherosclerosis, such as low density-lipoprotein receptor-deficient (LDLR-/-) and apolipoprotein E-deficient (apoE-/-) mice, and are used for studying pathophysiological mechanisms. Atherosclerotic lesions in the aortic valve and thoracic/abdominal aorta are commonly associated with hyperlipidemia. We recently demonstrated the development of large atherosclerotic plaques in Helicobacter pylori-infected heterozygous LDLR+/- apoE+/- mice.. To measure novel biomarkers related to atherosclerosis, blood coagulation, and oxidative stress in order to investigate their possible pathogenic roles in atherosclerosis-prone mice.. Mice were fed with a normal chow diet or high-fat diet and sacrificed at different age intervals to measure aortic plaque size. Plasma cholesterol was enzymatically measured. Enzyme-linked immunosorbent assay was used to measure oxidized LDL (oxLDL)/beta-2-glycoprotein I (beta2GPI) complexes, immunoglobulin M (IgM) antibodies against native LDL, oxLDL, or oxLDL/beta2GPI, and urine 11-dehydro-thromboxane B2 (11-dhTxB2) or 8-hydroxy-deoxyguanosine.. There was a parallel increase in plaque size, plasma cholesterol, and urinary 11-dhTxB2 in atherosclerosis-prone mice. In contrast to atherosclerosis-prone strains, an elevation of urinary 11-dhTxB2 with no significant plaque generation was observed in LDLR+/- 1 apoE+/- mice. The atherogenic autoantigen oxLDL/beta2GPI complex was detected only in LDLRI mice. These levels seem to depend on plaque size. IgM antibodies against oxLDL in apoE-/- mice were found, accompanied by atherosclerotic progression.. Progression of atherosclerotic lesions was associated not only with hypercholesterolemia but also with platelet activation and natural autoimmune-mediated regulatory mechanism(s) in murine models.

Topics: Animals; Apolipoproteins E; Atherosclerosis; beta 2-Glycoprotein I; Biomarkers; Disease Models, Animal; Immunity, Innate; Immunoglobulin M; Lipoproteins, LDL; Male; Mice; Oxidative Stress; Platelet Activation; Receptors, LDL; Thromboxane B2

Both F(2)-isoprostanes (8-iso-PGF(2alpha)), a well-known marker of oxidative stress, and thromboxanes A(2) (TXA(2)) are involved in atherosclerosis through LDL oxidation and platelet activation. Different aspects of the pathology can be described by 8-iso-PGF(2alpha) and TXA(2) so it is important to determine both their concentrations to monitor the disease progression and/or therapy effects. We developed a simple and sensitive method based on liquid chromatography-tandem mass spectrometry, using electrospray ionization in negative-ion mode, for the simultaneous measurement of the concentration of 8-iso-PGF(2alpha) and 11-dehydro thromboxane B(2) (11-DH-TXB(2)), a TXA(2) metabolite. This method was applied to analyze urine samples collected overnight from 15 atherosclerotic patients, with documented carotid artery sclerosis (CAS), and from 20 controls. The detection limit was 0.097pg/microL for 8-iso-PGF(2alpha) and 0.375pg/microL for 11-DH-TXB(2), with a linear range of 0.78-25pg/microL; the inter- and intraday imprecision was <5% for both metabolites. These analytes were higher in CAS (P<0.005 vs controls) and were positively correlated in patients but not in controls, even after adjustment for age and gender (r=0.60; P=0.032). This highly sensitive, precise, and rapid method allows for the simultaneous determination of 8-iso-PGF(2alpha) and 11-DH-TXB(2) in human urine samples in order to evaluate oxidative stress and platelet aggregation.

Topics: Aged; Atherosclerosis; Biomarkers; Chromatography, Liquid; Dinoprost; Female; Humans; Male; Middle Aged; Oxidative Stress; Platelet Aggregation; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry; Thromboxane A2; Thromboxane B2

To determine the fractalkine expression in the aorta of ApoE (-/-) mice and the effect of high-dose aspirin intervention on fractalkine expression and atherosclerotic lesion formation.. Twenty-one male ApoE gene knockout mice were randomized into three groups to receive either placebo in addition to normal mice chow (n = 7), placebo in addition to a high-fat diet (n = 7), or aspirin (58 mg/kg/d) in addition to a high-fat diet (n = 7). After 12 weeks of study, the mice were euthanized and serum cholesterol, thromboxane B(2), and 6-keto-PGF(1alpha) were examined. Fractalkine and cyclooxygenase expression in aorta were measured and the atherosclerotic lesion analyzed.. Pathology image analysis showed that the atherosclerotic plaque was the most extensive in the high-fat diet group while the addition of aspirin greatly reduced the severity of the plaque. Both RT-PCR analysis and immunohistochemical analysis showed that fractalkine expression was the strongest in the high-fat diet group and was significantly decreased by aspirin treatment. Serum thromboxane B(2) was lowered by aspirin while 6-keto-PGF(1alpha) and cholesterol remained unchanged.. The results of our study indicate that high dose aspirin can improve the atherosclerotic lesion and suppress the fractalkine expression in murine aorta.

Topics: Animals; Aorta; Apolipoproteins E; Aspirin; Atherosclerosis; C-Reactive Protein; Chemokine CX3CL1; Cholesterol; Cyclooxygenase 1; Cyclooxygenase 2; Dietary Fats; Gene Expression; Male; Membrane Proteins; Mice; Mice, Knockout; Prostaglandins F; Thromboxane B2; Triglycerides

Prostaglandin and thromboxane (TXA(2)) generation is increased in atherosclerosis. Studies with selective inhibitors attribute the enhanced prostacyclin (PGI(2)) generation to both cyclooxygenase-1 (COX-1) and COX-2 whereas the increased TXA(2) generation reflects platelet COX-1 expression. However, TXA(2) formation remains elevated in patients with cardiovascular disease on doses of aspirin that fully suppress platelet COX-1, suggesting other tissue sources for TXA(2) formation. Disruption of the thromboxane receptor gene suppresses the development of atherosclerosis. Notwithstanding this, the role of COX-1 in atherosclerosis is unclear, as it is widely distributed and contributes to a number of products, including those that potentially contribute to the resolution of inflammation.. We examined the role of COX-1 on prostaglandin generation, development of atherosclerosis and platelet-vessel wall interactions in the apoE(-/-) murine model by disrupting the COX-1 gene. ApoE(-/-)/COX-1(+/+), ApoE(-/-)/COX-1(+/-) and ApoE(-/-)/COX-1(-/-), were administered a 1% cholesterol diet for 8 weeks. Stable urinary metabolites of PGI(2) and TXA(2), which were markedly increased in the ApoE(-/-)/COX-1(+/+) were reduced by disruption of COX-1. Deletion of one or both copies of the COX-1 gene suppressed lesion formation. Assessment of platelet-vessel wall interactions by intravital microscopy showed a significant decrease in firm adhesion of platelets in the apoE/COX-1 double knockout (DKO).. COX-1 contributes to the enhanced formation of both PGI(2) and TXA(2) in atherosclerosis, and to the development of the disease. Non-platelet sources of COX-1 and TXA(2) that are inaccessible to standard doses of aspirin may contribute to the development of atherosclerosis.

Topics: Animals; Aorta, Thoracic; Apolipoproteins E; Atherosclerosis; Blood Platelets; Cyclooxygenase 1; Endothelium, Vascular; Female; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Biological; Thromboxane A2; Thromboxane B2

Chronic proliferative responses of different vascular cell types have been involved in the pathogenesis of atherosclerosis. However, their functional role remains to be established. Sirolimus reduces neointimal proliferation after balloon angioplasty and chronic graft vessel disease. These studies were undertaken to investigate the effects of this anti-proliferative drug on atherogenesis.. Low-density lipoprotein receptor-deficient (LDL r-KO) mice on a cholesterol-rich diet were randomized to receive placebo or sirolimus (0.1; 0.3; or 1 mg.kg(-1)) in their diet for 8 or 16 weeks.. In both studies, plasma levels of the drug increased in a dose-dependent fashion, animals gained weight normally and, among groups, plasma lipids levels did not differ significantly. Compared with placebo, plasma levels of interleukin-6, monocyte chemoattractant protein-1, interferon gamma, tumour necrosis factor alpha and CD40, and their mRNA levels in aortic tissue were significantly reduced in sirolimus-treated mice. This effect resulted in a significant and dose-dependent reduction in atherosclerotic lesions, in both the root and aortic tree. Also these lesions contained less monocyte/macrophages and smooth muscle cells, but more collagen.. The present results demonstrated that at low doses, sirolimus was an effective and safe anti-atherogenic agent in the LDL r-KO mice. It attenuated the progression of atherosclerosis and modulated the plaque phenotype by reducing the pro-inflammatory vascular responses typical of the disease.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta; Atherosclerosis; Cholesterol; Collagen; Creatinine; Cytokines; Diet, Atherogenic; Dose-Response Relationship, Drug; Inflammation; Isoprostanes; Male; Mice; Mice, Knockout; Random Allocation; Receptors, LDL; Sirolimus; Thromboxane B2; Time Factors; Triglycerides

Arachidonic acid's (AA) metabolites, eicosanoids, exert a tremendous influence on circulatory and vascular homeostasis, and in humans are generated by many organs and cell types. In this study we wanted to verify whether platelets AA metabolism play a significant role in pathogenesis of essential hypertension (EH). Participants were divided into the study (EH) and the control group. Plasma and urine concentrations of isoprostanes (8-iPF(2alpha)-III) and thromboxane B(2) (TxB(2)) were determined using the ELISA method. The levels of 5- and 12-hydroxyeicosatetraenoic (HETE) acids, generated by platelets, were analysed using RP-HPLC. In a suspension of not stimulated and AA-stimulated platelets TxB(2) level was statistically lower in the study than in the control group (p < 0.0001 and 0.001 respectively). The concentration of 12-HETE was significantly elevated in EH patients compared to the control group; however, only in the non-stimulated conditions (p < 0.05). Plasma and urine F2-isoprostanes levels were significantly higher in hypertensive individuals than in the control group (p < 0.00002 and p < 0.01 respectively). Moreover, EH patients excreted more TxB(2) in urine than normotensive individuals (p < 0.05). Our results highlight the mutual connections between the platelets AA metabolism and indicate its possible role in the pathogenesis of arterial hypertension. Moreover, we hypothesize that platelets AA metabolism may exert a pro-atherosclerotic effect. Finally, we suggest the use of (5-HETE+12-HETE)/TxB(2) parameter in further studies.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Adult; Arachidonic Acid; Atherosclerosis; Blood Platelets; Case-Control Studies; Humans; Hydroxyeicosatetraenoic Acids; Hypertension; Male; Middle Aged; Thromboxane B2

Cyclooxygenase-derived prostaglandins modulate cardiovascular disease risk. We genotyped 2212 Atherosclerosis Risk in Communities study participants (1,023 incident coronary heart disease (CHD) cases; 270 incident ischemic stroke cases; 919 non-cases) with available DNA for polymorphisms in PTGS1 and PTGS2. Using a case-cohort design, associations between genotype and CHD or stroke risk were evaluated using proportional hazards regression. In Caucasians, the reduced function PTGS1 -1006A variant allele was significantly more common among stroke cases compared to non-cases (18.2 versus 10.6%, P=0.027). In African Americans, the reduced function PTGS2 -765C variant allele was significantly more common in stroke cases (61.4 versus 49.4%, P=0.032). No significant relationships with CHD risk were observed. However, aspirin utilization appeared to modify the relationship between the PTGS2 G-765C polymorphism and CHD risk (interaction P=0.072). These findings suggest that genetic variation in PTGS1 and PTGS2 may be important risk factors for the development of cardiovascular disease events. Confirmation in independent populations is necessary.

Topics: Aspirin; Atherosclerosis; Biomarkers; Black or African American; Case-Control Studies; Coronary Disease; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Longitudinal Studies; Male; Middle Aged; Odds Ratio; Phenotype; Polymorphism, Single Nucleotide; Proportional Hazards Models; Prospective Studies; Risk Assessment; Risk Factors; Stroke; Thromboxane B2; United States; White People

Licofelone, a dual anti-inflammatory drug that inhibits 5-lipoxygenase (LOX) and cyclooxygenase (COX) enzymes, may have a better cardiovascular profile that cycloxygenase-2 inhibitors due to cycloxygenase-1 blockade-mediated antithrombotic effect and a better gastrointestinal tolerability. We examined the anti-inflammatory effect of licofelone on atherosclerotic lesions as well as in isolated neutrophils from whole blood of rabbits compared with a selective inhibitor of COX-2, rofecoxib. We also assessed the antithrombotic effect of licofelone in rabbit platelet-rich plasma. For this purpose, 30 rabbits underwent injury of femoral arteries, and they were randomized to receive 10 mg/kg/day licofelone or 5 mg/kg/day rofecoxib or no treatment during 4 weeks with atherogenic diet in all cases. Ten healthy rabbits were used as controls. Neutrophils and platelets were isolated from peripheral blood of rabbits for ex vivo studies. Licofelone reduced intima/media ratio in injured arteries, the macrophages infiltration in the neointimal area, monocyte chemoattractant protein-1 (MCP-1) gene expression, and the activation of nuclear factor-kappaB in rabbit atheroma. Moreover, licofelone inhibited COX-2 and 5-LOX protein expression in vascular lesions. Rofecoxib only diminished COX-2 protein expression and MCP-1 gene expression in vascular atheroma. Prostaglandin E(2) in rabbit plasma was attenuated by both drugs. Licofelone almost abolished 5-LOX activity by inhibiting leukotriene B4 generation in rabbit neutrophils and prevented platelet thromboxane B2 production from whole blood. Licofelone reduces neointimal formation and inflammation in an atherosclerotic rabbit model more markedly than rofecoxib. This effect, together with the antiplatelet activity of licofelone, suggests that this drug may have a favorable cardiovascular profile.

Topics: Acetates; Animals; Atherosclerosis; Chemokine CCL2; Cyclooxygenase Inhibitors; Dinoprostone; Disease Models, Animal; Leukotriene B4; Lipids; Lipoxygenase Inhibitors; Macrophages; Male; NF-kappa B; Pyrroles; Rabbits; RNA, Messenger; Thromboxane B2; Tunica Intima

COX-1-dependent eicosanoid formation accelerates atherogenesis, and low-dose aspirin reduces early atherosclerosis. However, the role of aspirin in modulating progression of vascular atherosclerotic lesions once established is less investigated. We wished to determine the effect of low-dose aspirin on vascular inflammation, plaque composition, and progression of established atherosclerosis. Low-density lipoprotein receptor-deficient mice (LDLR(-/-)) were fed a high-fat diet for 3 months. At this time, one group of mice underwent baseline analysis. Two additional groups, while continuing the high-fat diet, were randomized to receive placebo or aspirin for additional 3 months. At the end of the study, LDLR(-/-) mice that had received aspirin had suppressed biosynthesis of thromboxane B2, the major products of COX-1 activity, reduced monocyte chemoattractant protein-1, and soluble intercellular adhesion molecule-1 levels compared with controls. Compared with baseline, the placebo group had significant progression of atherosclerosis. In contrast, aspirin treated mice showed a significant reduction in progression of atherosclerosis, and a significant decrease in foam cell content. These results suggest that in murine atherosclerosis, low-dose aspirin retards progression of established and advanced vascular atherosclerotic lesions by suppressing the formation of bioactive lipids and vascular inflammation.

Topics: Animals; Aorta, Thoracic; Aspirin; Atherosclerosis; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Immunohistochemistry; Male; Mice; Receptors, LDL; Thromboxane B2; Treatment Outcome