thromboxane-a2 and Hyperlipidemias

Topics: Arrhythmias, Cardiac; Arteriosclerosis; Biomarkers; Cholesterol, VLDL; Coronary Restenosis; Docosahexaenoic Acids; Eicosapentaenoic Acid; Humans; Hyperlipidemias; Hypertension; Liver; Reference Values; Thrombosis; Thromboxane A2

Platelets contain three types of secretory organelles: the dense granules, the alpha granules, and the lysosomes. Most of the proteins secreted from platelets are stored in the alpha granules, whereas the dense granules contain substances such as adenine nucleotides, serotonin, Ca++, and inorganic pyrophosphate types as well as a heparatinase. Three of the secreted alpha granule proteins have been measured by radioimmunoassay and it has been suggested that levels of these proteins in patient plasmas provide an index of in vivo platelet activation and secretion. These three are beta-thromboglobulin, platelet factor 4, and thrombospondin. In this chapter the chemistry of these proteins will be considered briefly, as will their clearance from the circulation, and then the clinical studies will be reviewed critically. Since radioimmunoassays were developed for these proteins (the first was reported in 1975), there has been a profusion of reports on levels of one or another of these proteins in a wide range of disease states, and these reports have indicated secreted platelet protein levels ranging from normal to grossly elevated in a given disease state. Possible reasons for such variability will be discussed.

Topics: Angina, Unstable; Beta-Globulins; beta-Thromboglobulin; Blood Platelets; Catecholamines; Catheterization; Cerebrovascular Disorders; Coronary Disease; Coronary Vessels; Cytoplasmic Granules; Exercise Test; Female; Humans; Hyperlipidemias; Hypertension; Kidney Diseases; Myocardial Infarction; Platelet Factor 4; Pregnancy; Renal Dialysis; Thromboxane A2

Topics: Angina Pectoris; Animals; Arterioles; Blood Platelets; Blood Pressure; Coronary Circulation; Coronary Disease; Coronary Vessels; Epoprostenol; Humans; Hyperlipidemias; Microcirculation; Platelet Aggregation; Rheology; Spasm; Stress, Physiological; Stress, Psychological; Thromboxane A2; Vascular Resistance; Vasoconstriction

There is an abundance of information suggesting that prostaglandins are involved in the development and clinical expression of atherosclerosis. Many studies demonstrate a relationship between prostaglandins and the risk factors for peripheral and coronary artery disease. Thus, part of the mechanism by which hyperlipidemia, diabetes mellitus, smoking, hypertension, sex hormones, age, heredity, emotional stress and diet contribute to the development and progression of atherosclerosis may be through an imbalance between thromboxane A2 and prostaglandin I2. Recent studies show a temporal relationship between acute ischemic events (specifically, unstable angina) and a transcardiac increase in thromboxane B2, while others demonstrate a salutary effect of disaggregatory and vasodilatory prostaglandins in such patients. If prostaglandins and thromboxane prove important in ischemic vascular disease, attention will be directed at the correction of their pathologic imbalance. This may be accomplished by dietary manipulation as well as by the development of prostaglandin receptor antagonists or inhibitors of specific prostaglandin pathways.

Topics: Age Factors; Arteriosclerosis; Coronary Disease; Diabetes Mellitus; Diet; Epoprostenol; Gonadal Steroid Hormones; Humans; Hyperlipidemias; Hypertension; Prostaglandin Antagonists; Prostaglandins; Receptors, Prostaglandin; Risk; Smoking; Stress, Physiological; Thromboxane A2; Thromboxane B2

Cardiovascular disease (CVD) is a major contributor to the global burden of disease. Berberine, a long-standing, widely used, traditional Chinese medicine, is thought to have beneficial effects on CVD risk factors and in women with polycystic ovary syndrome. The mechanisms and effects, specifically in men, possibly via testosterone, have not been examined previously. To assess the effect of berberine on CVD risk factors and any potential pathway via testosterone in men, we conducted a randomized, double-blind, placebo-controlled, parallel trial in Hong Kong. In total, 84 eligible Chinese men with hyperlipidemia were randomized to berberine (500 mg orally, twice a day) or placebo for 12 weeks. CVD risk factors (lipids, thromboxane A2, blood pressure, body mass index and waist-hip ratio) and testosterone were assessed at baseline, and 8 and 12 weeks after intervention. We compared changes in CVD risk factors and testosterone after 12 weeks of intervention using analysis of variance, and after 8 and 12 weeks using generalized estimating equations (GEE). Of the 84 men randomized, 80 men completed the trial. Men randomized to berberine had larger reductions in total cholesterol (-0.39 mmol/L, 95% confidence interval (CI) -0.70 to -0.08) and high-density lipoprotein cholesterol (-0.07 mmol/L, 95% CI -0.13 to -0.01) after 12 weeks. Considering changes after 8 and 12 weeks together, berberine lowered total cholesterol and possibly low-density lipoprotein-cholesterol (LDL-c), and possibly increased testosterone. Changes in triglycerides, thromboxane A2, blood pressure, body mass index and waist-hip ratio after the intervention did not differ between the berberine and placebo groups. No serious adverse event was reported. Berberine is a promising treatment for lowering cholesterol. Berberine did not lower testosterone but instead may increase testosterone in men, suggesting sex-specific effects of berberine. Exploring other pathways and assessing sex differences would be worthwhile, with relevance to drug repositioning and healthcare.

Topics: Adult; Anticholesteremic Agents; Berberine; Blood Pressure; Body Mass Index; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Double-Blind Method; Heart Disease Risk Factors; Humans; Hyperlipidemias; Male; Middle Aged; Testosterone; Thromboxane A2; Triglycerides; Waist-Hip Ratio

To study the effects of Xuezhikang on lipid profile, thromboxane (TX) A(2), prostacyclin (PGI(2)) in patients with hyperlipidemia.. 91 patients with hyperlipidemia were randomly divided into a treatment group (n = 47, Xuezhikang 1.2 g/d Bid, p.o) and control group (n = 44, gemfibrozil 1.2 g/d Bid, p.o). serum lipids, TXB(2) and 6-Keto-PGF(1alpha) were determined before and 8 weeks after the treatment.. (1) After 8 weeks of treatment, the level of serum total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) decreased by 21.6% (P < 0.01) and 33.3% (P < 0. 01) in the Xuezikang group and by 20.4% (P < 0.01) and 24.8% (P < 0.01) in the gemfibrozil group respectively. Serum high density lipoprotein cholesterol (HDL-C) level elevated by 33.7% in the Xuezhikang group (P < 0.01) and 26.9% in the gemfibrozil group (P < 0.01). The effect of Xuezhikang was the same as gemfibrozil. There was no statistically significant difference between the effects of these two drugs. Triglyceride (TG) level decreased by 23.3% in the Xuezhikang group (P < 0.01) and 40.3% in the gemfibrozil group (P < 0.01). TG lowering effect of gemfibrozil was superior to that of Xuezhikang (P < 0.05). (2) The level of lipoprotein (a) [LP (a)] in the plasma decreased by 28.2% (P < 0.01) in the Xuezhikang group and by 4.9% (P > 0.05) in the gemfibrozil group. LP (a) lowering effect of Xuezhikang was superior to that of gemfibrozil (P < 0.01). (3)The Level of thromboxane (TX) B(2) in the plasma decreased by 34.2% in the Xuezhikang group (P < 0.01) and by 8.4% in the gemfibrozil group (P < 0.01). TXB(2) lowering effect of Xuezhikang was superior to that of gemfibrozil (P < 0.01). The level of 6-KetO-PGF(1alpha) in the plasma elevated by 65.4% in the Xuezhikang group (P < 0.01) and by 11.7% in the gemfibrozil group (P < 0.01); the effect of Xuezhikang was superior to that of gemfibrozil (P < 0.01).. Xuezhikang could markedly decrease the level of TC and LDL-C and elevate that of HDL-C in patients with hyperlipidemia and the effects of Xuezhikang were the same as those of gemfibrozil. TG lowering effect of gemfibrozil was superior to that of Xuezhikang, but Xuezhikang could markedly decrease the level of Lp (a) and regluate the balance between TXA(2) and PGI(2), its effect being superior to that of gemfibrozil.

Topics: Aged; Drugs, Chinese Herbal; Epoprostenol; Female; Gemfibrozil; Humans; Hyperlipidemias; Hypolipidemic Agents; Lipids; Male; Middle Aged; Phytotherapy; Thromboxane A2

Background and Purpose- Hyperlipidemia is associated with platelet hyperreactivity. We hypothesized that L-4F, an apolipoprotein A-I mimetic peptide, would inhibit platelet aggregation in hyperlipidemic mice.. Injecting L-4F into apolipoprotein E (apoE)-null and low-density lipoprotein receptor-null mice resulted in a significant reduction in platelet aggregation in response to agonists; however, there was no reduction in platelet aggregation after injection of L-4F into wild-type (WT) mice. Consistent with these results, injection of L-4F into apoE-null mice prolonged bleeding time; the same result was not found in WT mice. Incubating L-4F in vitro with apoE-null platelet-rich plasma also resulted in decreased platelet aggregation. However, incubating washed platelets from either apoE-null or WT mice with L-4F did not alter aggregation. Compared with WT mice, unstimulated platelets from apoE-null mice contained significantly more 12-hydroxy 5,8,10,14-eicosatetraenoic acid, thromboxane A(2), and prostaglandins D(2) and E(2). In response to agonists, platelets from L-4F-treated apoE-null mice formed significantly less thromboxane A(2), prostaglandins D(2) and E(2), and 12-hydroxy 5,8,10,14-eicosatetraenoic acid.. By binding plasma-oxidized lipids that cause platelet hyperreactivity in hyperlipidemic mice, L-4F decreases platelet aggregation.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Adenosine Diphosphate; Animals; Apolipoprotein A-I; Apolipoproteins E; Arachidonic Acid; Blood Coagulation; Collagen; Dinoprostone; Disease Models, Animal; Hyperlipidemias; Injections, Subcutaneous; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Mimicry; Peptides; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Prostaglandin D2; Receptors, LDL; Thromboxane A2

We compared the impact of hypercholesterolaemia and mixed dyslipidaemia on vascular function, vascular structure and fibrinolytic balance in rabbits. To this end, vascular reactivity was studied in aortic rings from rabbits fed a control diet, a diet containing 0.5% cholesterol+14% coconut oil (mixed dyslipidaemia) or a diet containing 1% cholesterol (hypercholesterolaemia) for 12-14 weeks. Morphometric analysis of aorta was also performed and plasminogen activator inhibitor-1 (PAI-1) as well as tissue-type plasminogen activator (t-PA) plasma activities were measured. Both diets induced a similar increase in cholesterol plasma levels, although triacylglycerols (triglycerides) were increased in animals with mixed dyslipidaemia. Hypercholesterolaemia was associated with intimal thickening, reduction in acetylcholine-induced relaxation ( P <0.05) and increased vasoconstriction induced by acetylcholine+ N (G)-nitro-L-arginine methyl ester (L-NAME) when compared with controls ( P <0.05). These effects were more marked ( P <0.05) in animals with mixed dyslipidaemia. Incubation with ifetroban, a thromboxane A(2)/prostaglandin H(2) receptor antagonist, increased acetylcholine-induced relaxation ( P <0.05) and reduced acetylcholine+L-NAME contraction ( P <0.05) in both diet groups. In contrast, the presence of PD 145, an endothelin (ET)(A)/ET(B) receptor antagonist, exerted these effects only in rabbits with mixed dyslipidaemia. Both hypercholesterolaemia and mixed dyslipidaemia induced a similar increase in PAI-1 and a similar decrease in t-PA plasma activities. These data suggest that hypertriglyceridaemia can increase the deleterious effects of hypercholesterolaemia on endothelial function and vascular structure. This additional harmful effect exerted by triacylglycerols on endothelial function could, in part, be mediated by ET.

Topics: Acetylcholine; Animals; Aorta; Arteriosclerosis; Bridged Bicyclo Compounds, Heterocyclic; Diet; Endothelium, Vascular; Enzyme Inhibitors; Fibrinolysis; Hypercholesterolemia; Hyperlipidemias; Hypertriglyceridemia; In Vitro Techniques; Male; Models, Animal; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Oxazoles; Plasminogen Activator Inhibitor 1; Rabbits; Thromboxane A2; Tissue Plasminogen Activator; Vasoconstrictor Agents

Prostacyclin (PGI2), thromboxane A2 (TXA2) and F2-isoprostanes, prostaglandin F2-like compounds, have wide and contrasting spectrum of biological activities and may influence blood pressure and atherogenesis. To investigate the dynamics of PGI2, TXA2 and F2-isoprostanes in patients with hypertension and hyperlipidemia (HH group), we measured the major urinary metabolites of PGI2: 6-keto PGF1alpha (Keto) and 2,3-dinor-6-keto PGF1alpha, (Dinor), those of TXA2:TXB2 and 11-dehydro TXB2 (Dehydro), and urinary 8-isoprostane (Iso) in 34 patients. Urinary excretion of Dinor was significantly lower in patients than in controls and that of Dehydro was significantly higher in patients than in controls. Keto, TXB2 and Iso were not significantly different between them. Antiplatelet agents decreased not only TXA2 metabolites but also PGI2 metabolites. Urinary C-peptide immunoreactivity was correlated with Dinor and Dehydro. After administration of eicosapentaenoic acid (EPA), total cholesterol (T-cho) and triglycerides (TG) significantly decreased. Although prostanoids did not show significant change, changes in T-cho were correlated with changes in Dinor and changes in Iso. These results suggest that PGI2 and TXA2 of systemic origin might be related to the pathophysiology of hypertension and hyperlipidemia and that the dynamics of PGI2, TXA2 and F2-isoprostanes might be related to not only blood pressure regulation but also lipid and glucose metabolism.

Topics: Aspirin; Dinoprost; Dipyridamole; Eicosapentaenoic Acid; Epoprostenol; Humans; Hyperlipidemias; Hypertension; Platelet Aggregation Inhibitors; Thromboxane A2; Ticlopidine

The study was performed to investigate the influence of lipoproteins (LP) on the thromboxane (TX) A2 formation capacity of platelets in clotting whole blood in vitro. The different lipoprotein fractions VLDL, LDL, HDL2 and HDL3 were isolated from blood of normo- or dyslipidemic volunteers by ultracentrifugation. These lipoproteins were incubated in blood with different levels of serum total cholesterol (TC) taken from normolipidemics (TC < 200 mg/dl), moderate hypercholesterolemics (TC: 200-250 mg/dl) or subjects with high cholesterol level (TC > 250 mg/dl), respectively. The amount of serum TXA2 formed within 60 min at 37 degrees C was measured by enzyme immunoassay. The results obtained show that the efficacy of separate LP fractions to influence the TXA2 production depends not only on the type of LP fraction but also on the source of plasma used for isolation of LP and on the cholesterol level in the blood for incubation: LDL taken from normolipidemics or moderate hyperlipidemics inhibited the TXA2 formation in blood from normolipidemics (P < 0.02, respectively), but enhanced it in blood from persons with moderate hypercholesterolemia (P < 0.05). LDL from hyperlipidemics enhanced TXA2 production in blood from hyperlipidemics (P < 0.05). The HDL2 fractions inhibited the TXA2 formation in blood from normo- and hypercholesterolemics (P < 0.02, resp.), but there was no effect of HDL2 in clotting blood from persons with moderate hypercholesterolemia. All HDL3 fractions tested inhibited the TXA2 formation in all types of blood used for clotting (P < 0.02, resp.), probably due to their great cholesterol accepting capacity.

Topics: Blood Coagulation; Blood Platelets; Humans; Hypercholesterolemia; Hyperlipidemias; In Vitro Techniques; Lipoproteins; Thromboxane A2; Thromboxane B2

The effects of ethanol on platelets from rabbits with two different types of hypercholesterolemia, diet-induced and genetically determined, were investigated. There were no differences between the hypercholesterolemic groups and their controls in the extent of (primary) ADP-induced aggregation of washed platelets, and this aggregation was not inhibited by ethanol. Platelets from cholesterol-fed rabbits were more sensitive to aggregation and secretion induced by collagen, whereas platelets from Watanabe heritable hyperlipidemic (WHHL) rabbits were less sensitive. Ethanol inhibited collagen-induced responses of platelets from both hypercholesterolemic groups, but the extent of inhibition of aggregation was not different compared with controls. Because ethanol did not affect U46619-induced responses of aspirin-treated platelets, ethanol does not inhibit aggregation and secretion stimulated by collagen via an effect on thromboxane A2 (TxA2)-induced responses. Platelets from cholesterol-fed rabbits were more sensitive to thrombin even when TxA2 formation was blocked by aspirin, and inhibition of aggregation by ethanol was less in cholesterol-fed rabbits than in controls. However, neither the extent of thrombin-induced responses nor the inhibitory effect of ethanol was different in platelets from WHHL rabbits compared with controls. Thus, different etiologies of hypercholesterolemia produce different changes in platelet function, and ethanol has different effects on the platelets from cholesterol-fed rabbits compared with the platelets from WHHL rabbits. The inhibitory effect of ethanol on the thrombin-induced aggregation of platelets from cholesterol-fed rabbits is attenuated compared with controls, and this finding contrasts with the reported greater inhibitory effect of ethanol on platelets enriched with saturated fats.

Topics: Adenosine Diphosphate; Animals; Aspirin; Blood Platelets; Cholesterol, Dietary; Collagen; Ethanol; Hyperlipidemias; Male; Platelet Aggregation; Prostaglandin Endoperoxides, Synthetic; Rabbits; Thrombin; Thromboxane A2

Topics: Arachidonic Acid; Arteriosclerosis; Blood Platelets; Cell Membrane; Humans; Hyperlipidemias; Membrane Lipids; Platelet Aggregation; Prostaglandins; Thromboxane A2

Normotensive rats of the Milan strain (MNS) spontaneously develop focal glomerulosclerosis. In order to explore the contribution of glomerular thromboxane (TX) A2 synthesis to the development of the disease, we have characterized the time course of renal functional and biochemical changes, and their modification by long-term treatment with a TX-synthase inhibitor. Oral administration (150 mg.kg-1 from 1 to 14 months of age) of FCE 22178 suppressed enhanced glomerular TXB2 production at all experimental times (mean inhibition 80%) and proteinuria (varying between 27.1 and 73.0%) while preserving renal blood flow and glomerular filtration rate. These effects of TX-synthase inhibition were seen in the absence of any statistically significant changes in systemic blood pressure. Moreover, FCE 22178 had no antihypertensive effects in hypertensive rats of the Milan strain (MHS) nor in spontaneously hypertensive rats (SHR). Treatment also prevented the age-related hypoalbuminemia and hyperlipidemia observed in control MNS and significantly (P less than 0.01) reduced glomerular histologic damage, as demonstrated by light microscopy studies and measurement of sclerotic area. We conclude that: 1) MNS rats provide an animal model of long-lasting proteinuria characterized by an age-related increase in glomerular TXB2 production paralleled by progressive loss of renal structural integrity and function and by a secondary dyslipidemia; 2) pharmacological inhibition of glomerular TX-synthase attenuates the structural as well as the functional expression of kidney disease, without a primary effect on systemic blood pressure. These data are suggestive of an important modulating role of TXA2 in the progression of MNS renal disease.

Topics: Animals; Glomerulosclerosis, Focal Segmental; Hyperlipidemias; Hypertension; Imidazoles; Kidney Glomerulus; Male; Naphthalenes; Rats; Rats, Inbred SHR; Thromboxane A2; Thromboxane-A Synthase; Time Factors

In young patients with borderline arterial hypertension and, to a greater extent, with Stage 1 hypertensive disease (HD), changes were found in the proatherogenic plasma lipid and apoprotein composition, which were manifested as higher levels of total cholesterol, triglycerides, low and very low density lipoprotein cholesterols along with increased apolipoprotein B and apolipoprotein B:apolipoprotein AI ratio. The prostacyclin-thromboxane system in borderline arterial hypertension was in an activated state by retaining the physiological ratio of its components. The patients with Stage I HD exhibited a considerable increase in thromboxane activity, which determined the system's imbalance towards its predominance. In Stage I HD, the thrombocytic link of hemostasis was characterized by enhanced platelet aggregability mediated by the imbalance of the prostacyclin-thromboxane system in the direction of thromboxane.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Arteriosclerosis; Epoprostenol; Female; Humans; Hyperlipidemias; Hypertension; Lipids; Male; Platelet Aggregation; Thromboxane A2; Thromboxane B2; Time Factors

An increased lipid peroxides and a decreased production of prostacyclin have been shown in advanced atherosclerotic lesions and plasma. Our purpose was to determine whether the similar findings could be observed in cultured endothelial cells, and whether antioxidants could protect the cell against peroxide injury. In these experiments we have used bovine aortic endothelial cells in culture to address the issue of hyperlipidemia-induced arterial damage. Results of the present study showed that different concentration of hyperlipidemic sera from atherogenic rabbits induced a time- and dose-dependent alteration in the production of prostacyclin and levels of lipid peroxides in endothelial cells. Endothelial cells incubated with hyperlipidemic serum increased prostacyclin generation significantly during the initial stages and then continuously decreased. When endothelial cells were incubated for 36 h, TXA2 generation was also impaired and at the same time the cellular lipid peroxides content increased. There was a positive correlation between the concentration of hyperlipidemic serum and lipid peroxides and an inverse correlation with prostacyclin synthesis. The medium supplemented with antioxidant selenium or vitamin E showed a significant decrease in lipid peroxides and an increase in prostacyclin synthesis. These results suggest that both hyperlipidemic serum and lipid peroxides injury endothelial cells and inactivate prostacyclin synthetase, resulting in a decrease of prostacyclin production, while antioxidants have a protective effect. We conclude that the increase in lipid peroxides in association with hyperlipidemia results in alteration of prostacyclin synthesis that may play an important role in the pathogenesis of atherosclerosis.

Topics: Animals; Antioxidants; Aorta; Cattle; Cells, Cultured; Endothelium, Vascular; Epoprostenol; Hyperlipidemias; Kinetics; Lipid Peroxidation; Rabbits; Selenium; Thromboxane A2; Vitamin E

Topics: Animals; Arteriosclerosis; Drugs, Chinese Herbal; Epoprostenol; Hyperlipidemias; Lipid Peroxides; Male; Rabbits; Thromboxane A2

Topics: Arachidonic Acid; Arachidonic Acids; Female; Gestational Age; Humans; Hyperlipidemias; Pregnancy; Pregnancy Complications; Thromboxane A2; Triglycerides

Topics: Alprostadil; Angioplasty, Balloon; Anti-Bacterial Agents; Anticoagulants; Arterial Occlusive Diseases; Arteriosclerosis; Aspirin; Dipyridamole; Endarterectomy; Exercise Therapy; Fibrinolysis; Humans; Hyperlipidemias; Hypertension; Infusions, Intra-Arterial; Intermittent Claudication; Prostaglandins E; Serotonin Antagonists; Sympathectomy; Thromboxane A2