15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and Atherosclerosis

Thromboxane A

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Aorta; Atherosclerosis; Benzimidazoles; Cell Adhesion; Cell Survival; Human Umbilical Vein Endothelial Cells; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Knockout, ApoE; Reactive Oxygen Species; Receptors, Thromboxane A2, Prostaglandin H2

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Alprostadil; Atherosclerosis; Blood Platelets; Cardiovascular System; Dose-Response Relationship, Drug; Humans; P-Selectin; Platelet Activating Factor; Platelet Aggregation; Receptors, Prostaglandin E

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

The plasma level of soluble CD40 ligand (sCD40L), which induces pro-inflammatory and pro-atherogenic responses, is known to be elevated in atherosclerotic patients. In this study, we investigated the mechanism of sCD40L release from human platelets, focusing on the involvement of thromboxane (TX) A(2).. We measured sCD40L release and TXA(2) production induced by ristocetin, an activator of GPIb/IX/V, from human platelets in vitro. Moreover, plasma sCD40L and TXA(2) levels in the 10 patients with severe carotid artery stenosis who were not taking any anti-platelet medicines were measured and compared with those obtained from non-atherosclerotic controls.. Ristocetin significantly promoted sCD40L release and TXA(2) generation from platelets in vitro. Aspirin and SC-560, a cyclooxygenase-1 inhibitor, suppressed the ristocetin-induced sCD40L release from platelets in parallel with TXA(2) production. Ozagrel, a TXA(2) synthase inhibitor and PTXA(2), a thromboxane receptor (TP) antagonist also suppressed sCD40L release. U46619, a TP agonist, reversed the suppressive effect of aspirin on sCD40L release. In vivo, plasma levels of sCD40L and TXA(2) in the patients were significantly higher than those in controls. Elevated plasma levels of TXA(2) and sCD40L in the patients were markedly diminished after 7 days of 100mg aspirin administration.. These results strongly suggest that GPIb/IX/V activation induces sCD40L release via TXA(2) from human platelets, and that sCD40L release via TXA(2) generation from platelets in atherosclerotic patients are up-regulated.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Aged; Aspirin; Atherosclerosis; Blood Platelets; Carotid Artery Diseases; CD40 Ligand; Female; Humans; Male; MAP Kinase Kinase 4; Methacrylates; Middle Aged; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Pyrazoles; Ristocetin; Thromboxane A2

Early manifestations of kidney disease occur in atherosclerosis and activation of TP (thromboxane A(2)) receptors is implicated in atherosclerotic, diabetes, and renal diseases. The purpose of the present study was to analyze, in isolated, perfused mouse kidneys, the participation of TP receptors in renal vasoconstrictions and vasodilatations. In kidneys, taken from wild-type C57BL6, apolipoprotein E-deficient (ApoE-KO) and diabetic ApoE-KO mice, changes in perfusion pressure were recorded. Constrictions to TP receptor ligands U 46619, arachidonic acid, PGH(2), and 8-iso-PGF(2alpha), but not those to angiotensin II, endothelin, or norepinephrine, were inhibited by the selective TP receptor antagonist Triplion (S 18886; 10 nM). Acetylcholine and prostacyclin evoked biphasic responses during methoxamine constrictions; the constrictor part was blocked by Triplion. In ApoE-KO mouse kidneys, compared with C57BL6, a specific decrease in norepinephrine response and no modification in dilator responses were observed. In diabetic ApoE-KO mouse kidneys, constrictions to U 46619 and those to 8-iso-PGF(2alpha) were significantly and selectively augmented, without modification in the expression of the TP receptor, and again without any significant change in vasodilator activity. Thus TP receptors are functional, and their activation is not involved in norepinephrine, endothelin, and angiotensin II vasoconstrictions but is implicated in the unusual vasoconstrictions to acetylcholine and prostacyclin. Increased responsiveness of TP receptors occurs in diabetic ApoE-KO mouse kidneys. Thus early changes in TP receptor-mediated vasoconstrictor activity may participate in the development of kidney disease in atherosclerosis and diabetes.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Animals; Apolipoproteins E; Atherosclerosis; Diabetes Mellitus, Experimental; Dinoprost; Disease Models, Animal; Epoprostenol; Kidney; Male; Methoxamine; Mice; Mice, Inbred C57BL; Mice, Knockout; Naphthalenes; Propionates; Receptors, Thromboxane A2, Prostaglandin H2; Streptozocin; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents