thromboxane-a2 and Vasculitis

Prostanoids play a critical role in clinical areas such as inflammation, thrombosis, immune response, and cancer. Although some studies suggest that there are genes that determine variability of some prostanoid-related phenotypes, the genetic influence on these traits has not been evaluated.. The relative contributions of genetic and environmental influences to the prostanoid biosynthetic pathway-related phenotypes, cyclooxygenase isoenzymes, microsomal-PGE-synthase-1 and TxA-synthase expression, and thromboxane-A(2) and prostaglandin-E(2) production by stimulated whole blood, were assessed in a sample of 308 individuals in 15 extended families. The effects of measured covariates (such as sex, age, and smoking), genes, and environmental variables shared by members of a household were quantified. Heritabilities ranging from 0.406 to 0.634 for enzyme expression and from 0.283 to 0. 751 for prostanoid production were found.. These results demonstrate clearly the importance of genetic factors in determining variation in phenotypes that are components of the prostanoid biosynthetic pathways. The presence of such strong genetic effects suggest that it will be possible to localize previously unknown genes that influence quantitative variation in these phenotypes, some of which affect multiple aspects of cell biology, with important clinical implications.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Vessels; Child; Child, Preschool; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprostone; Environment; Enzymes; Female; Gene Expression Regulation, Enzymologic; Humans; Intramolecular Oxidoreductases; Male; Middle Aged; Phenotype; Platelet Count; Prostaglandin-E Synthases; Spain; Thromboxane A2; Thromboxane-A Synthase; Vasculitis; Young Adult

Suppression of thromboxane (Tx) A(2) biosynthesis retards atherogenesis. In this setting, the coincidental presence of nonconventional ligands for the TxA(2) receptor (TP), such as isoprostanes, could still induce a proatherogenic vascular phenotype. However, no data are available on the effect of combining suppression of TxA(2) formation with blockade of TP in atherogenesis. To this end, we tested the effect of a selective COX-1 inhibitor, SC560, a TP antagonist, BM-573, or a combination of both in low-density lipoprotein receptor-deficient mice on a high-fat diet. None of the treatments affected body weight or plasma cholesterol or triglycerides levels. Although SC-560 suppressed TxA(2) biosynthesis, BM-573 reduced its levels by 35%; in contrast, the 2 drugs, alone or in combination, did not significantly affect prostacyclin levels. At the end of the study, SC560 and BM-573 reduced atherogenesis; however, a further significant decrease was observed in mice receiving both drugs. This effect was associated with a further significant reduction of vascular inflammation, a decrease in macrophages, and an increase in the content of collagen and smooth muscle cells of the atherosclerotic lesions. These results show for the first time that the addition of a TP antagonist increases the antiatherogenic effect of COX-1-dependent TxA(2) suppression.

Topics: Animals; Atherosclerosis; Cholesterol; Collagen; Cyclooxygenase 1; Epoprostenol; Macrophages; Membrane Proteins; Mice; Mice, Knockout; Myocytes, Smooth Muscle; Pyrazoles; Receptors, LDL; Receptors, Thromboxane A2, Prostaglandin H2; Sulfonylurea Compounds; Thromboxane A2; Triglycerides; Vasculitis

We analyzed the involvement of thromboxane (TX) A2/prostaglandin (PG) H2 (TP) receptor in ischemia-induced neovascularization in mice.. Unilateral hindlimb ischemia was induced by right femoral artery ligature in male C57BL/6J mice (n=7 per group). Animals were then treated with or without TP receptor antagonist (S18886, 5 or 10 mg/kg per day; ramatroban, 10 mg/kg per day) or aspirin (30 mg/kg per day) in drinking water for 21 days. Hindlimb ischemia raised plasma level of TXB2, the stable metabolite of TXA2, by 4.7-fold. This increase was blocked by aspirin treatment whereas S18886 (5 or 10 mg/kg per day) had no effect. However, neither S 18886 nor aspirin affected postischemic neovascularization. We next assessed the putative involvement of TXA2 signaling in angiotensin II (Ang II) proangiogenic pathway. Ang II (0.3 mg/kg per day) enhanced TXB2 plasma levels by 2.6-fold over that of control (P<0.01). Ang II-induced TXB2 upregulation was reduced by cotreatment with Ang II type I receptor antagonist (candesartan, 20 mg/kg per day). Angiographic score, capillary number, and foot perfusion were improved by 1.7-, 1.7-, and 1.4-fold, respectively, in Ang II-treated mice compared with controls (P<0.05). Ang II proangiogenic effect was associated with a 1.6-fold increase in VEGF-A protein content (P<0.05) and a 1.4-fold increase in the number of Mac-3-positive cells (ie, macrophages) in ischemic areas (P<0.05). Interestingly, treatments with TP receptor antagonists or aspirin hampered the proangiogenic effects of Ang II.. Endogenous activation of TXA2 receptor by eicosanoids did not modulate spontaneous neovascularization in the setting of ischemia. Conversely, TXA2 signaling is involved in Ang II-induced AT1-dependent vessel growth.

Topics: Angiotensin II; Animals; Capillaries; Hindlimb; Ischemia; Male; Mice; Mice, Inbred C57BL; Naphthalenes; Neovascularization, Physiologic; Propionates; Receptors, Thromboxane A2, Prostaglandin H2; Signal Transduction; Thromboxane A2; Thromboxane B2; Vasculitis; Vasoconstrictor Agents

Mice of the autoimmune strain MRL/1, the congenic strain MRL/n, and two control strains, Balb/c and C57BL/6 mice, were fed diets which varied in the content of lipid and cholesterol. Serum cholesterol levels were highest in mice fed diets containing cholesterol and lowest in mice fed laboratory "chow." Animals fed diets that increased serum cholesterol had decreased production of prostacyclin by vascular tissue and increased production of thromboxane A2 by platelets. Prostacyclin production by heart tissue in response to arachidonic acid showed a negative correlation (r = -0.86) with serum cholesterol. In contrast, serum thromboxane demonstrated a positive correlation (r = 0.70) with serum cholesterol. The prevalence of autoimmune vasculitis seen in MRL/lpr mice was not affected by diet. However, MRL/lpr mice fed a high-fat, cholesterol-containing diet had intimal vascular lesions containing foam cells typical of arteriosclerosis. It is suggested that diets that raise serum cholesterol may influence the nature of autoimmune-mediated vascular disease by altering the balance between thromboxane and prostacyclin.

Topics: Animal Nutritional Physiological Phenomena; Animals; Autoimmune Diseases; Blood Platelets; Blood Vessels; Cholesterol; Cholesterol, Dietary; Dietary Fats; Epoprostenol; Longevity; Male; Mice; Mice, Mutant Strains; Rats; Thromboxane A2; Thromboxanes; Vasculitis