Terutroban et récepteurs TP endothéliaux dans l’athérogenèse

Le traitement des maladies thrombotiques implique l’utilisation de substances antiplaquettaires, anti-coagulantes ou profibrinolytiques. L’action antiplaquettaire de l’aspirine est due à l’inhibition indirecte de la production du thromboxane A2 (TXA2), un puissant vasoconstricteur également activateur des plaquettes. Le terutroban (S 18886), quant à lui, agit plus spécifiquement comme antagoniste sélectif des récepteurs TP, les récepteurs du TXA2 qui, dans le système vasculaire, se trouvent sur les plaquettes, les cellules musculaires lisses et l’endothélium. Les études précliniques et cliniques effectuées avec le terutroban ont démontré ses effets antithrombotiques. Le but de cette revue est de résumer le rôle des récepteurs TP endothéliaux dans l’athérogenèse et de décrire les études qui, menées avec le terutroban, ont contribué à établir ce rôle. En effet, l’activation des récepteurs TP endothéliaux, en provoquant l’expression de molécules d’adhérence qui favorisent l’adhérence et l’infiltration de monocytes/macrophages dans la paroi artérielle, participe à la genèse de l’athérosclérose.Treatment of thrombotic diseases implicates the use of anti-platelet agents, anti-coagulants and pro-fibrinolytic substances. Amongst the anti-platelet drugs, aspirin occupies a unique position. As soon as it became evident that the major action of aspirin is indirect blockade, through inhibition of cyclooxygenase (COX), of the production of thromboxane A2 (TXA2), a powerful vasoconstrictor and platelet activator, research for new anti-thrombotics that interact more specifically with the production and/or the action of TXA2 was started. Terutroban (S 18886) is a selective antagonist of TP receptors, the receptors for TXA2, that are present on platelets and on vascular smooth muscle cells, but also on endothelial cells. The role played by the platelet and smooth muscle cell TP receptors in thrombotic disease is well known, and preclinical and clinical studies with terutroban have illustrated the powerful antithrombotic effects of this agent. The implication of endothelial TP receptors in the development of atherosclerotic disease has only been examined during the past five years and studies with terutroban have been crucial for understanding the role of these endothelial receptors in cardiovascular physiopathology. The goal of the present review is to discuss the arguments in favour of the hypothesis suggesting that activation of endothelial TP receptors, by causing expression of adhesion molecules, favours adhesion and infiltration of monocytes/macrophages in the arterial wall, thereby stimulating the development of atherosclerosis. The review will also highlight the important contribution of the studies performed with terutroban in this research area. The triple activity (anti-thrombotic, anti-vasoconstrictor, anti-atherosclerotic) observed with terutroban in preclinical studies, stressed by the first results in clinical development, places terutroban as an innovative drug with a unique potential for treatment of cardiovascular disorders

The induction of heme oxygenase 1 decreases contractility in human internal thoracic artery and radial artery grafts

ObjectiveSpasm remains a potential problem encountered during the use of arterial grafts in coronary artery bypass surgery. Heme oxygenase plays a role in the control of arterial vasoreactivity. Heme oxygenase exists in 2 constitutive isoforms (heme oxygenase 2 and 3) and an inducible isoform (heme oxygenase 1). The aim of our study was to induce heme oxygenase 1 by using hemin in human internal thoracic and radial arteries and to evaluate the effect of this induction on the contractility of these arterial grafts.MethodsSegments of human arterial grafts obtained from patients undergoing isolated coronary artery bypass surgery were incubated in organ chambers for 4 hours in the presence of 10−4 mol/L hemin. Concentration-response curves to norepinephrine were obtained in control and hemin-treated arterial rings. Heme oxygenase 1 expression was evaluated by using enzyme-linked immunosorbent assays and immunohistochemical staining.ResultsThe contractility of the arterial rings to norepinephrine was significantly reduced after incubation with hemin. Zinc protoporphyrin (an inhibitor of heme oxygenase) reversed the effect of hemin, whereas the inhibitor of nitric oxide synthase had no effect. The inhibitor of soluble guanylate cyclase blocked the decrease in contractility induced by hemin. Immunohistochemical staining revealed a large expression of heme oxygenase 1 in all vascular layers of hemin-treated internal thoracic artery and radial artery rings. Enzyme-linked immunosorbent assay studies showed a significant increase in heme oxygenase 1 levels in hemin-treated internal thoracic artery and radial artery rings.ConclusionHemin caused in vitro induction of heme oxygenase 1 in human internal thoracic artery and radial artery grafts. This induction resulted in a reduced contractility to norepinephrine, partially through the cyclic guanosine monophosphate–dependent pathway. This effect was independent from nitric oxide synthesis

AMPK Phosphorylates and Inhibits SREBP Activity to Attenuate Hepatic Steatosis and Atherosclerosis in Diet-Induced Insulin-Resistant Mice

SummaryAMPK has emerged as a critical mechanism for salutary effects of polyphenols on lipid metabolic disorders in type 1 and type 2 diabetes. Here we demonstrate that AMPK interacts with and directly phosphorylates sterol regulatory element binding proteins (SREBP-1c and -2). Ser372 phosphorylation of SREBP-1c by AMPK is necessary for inhibition of proteolytic processing and transcriptional activity of SREBP-1c in response to polyphenols and metformin. AMPK stimulates Ser372 phosphorylation, suppresses SREBP-1c cleavage and nuclear translocation, and represses SREBP-1c target gene expression in hepatocytes exposed to high glucose, leading to reduced lipogenesis and lipid accumulation. Hepatic activation of AMPK by the synthetic polyphenol S17834 protects against hepatic steatosis, hyperlipidemia, and accelerated atherosclerosis in diet-induced insulin-resistant LDL receptor-deficient mice in part through phosphorylation of SREBP-1c Ser372 and suppression of SREBP-1c- and -2-dependent lipogenesis. AMPK-dependent phosphorylation of SREBP may offer therapeutic strategies to combat insulin resistance, dyslipidemia, and atherosclerosis

Experimental Models of Thrombosis and Atherosclerosis

Atherothrombosis is a complex disease which includes two different pathologies: atherosclerosis, the process of plaque formation in the arterial wall and thrombosis, the formation of a blood clot mostly at the site of a ruptured atherosclerotic lesion. Animal models for both pathologies have been useful to understand their aetiology and their evolution and they were used to evaluate the efficacy of new treatments. Numerous models to study venous and arterial thrombosis have been described. Thus in the rat, venous thrombosis induced by lesion/stasis, e.g. in the vena cava, and arterial thrombosis by lesioning of the vessel wall are frequently used. The resulting blood clot formation is measured either directly (weight of the thrombus) or indirectly (reduction in blood flow). More complex models have been developed in large animals such as dogs and pigs in order to examine coronary thrombosis; the principle always being the arterial lesion that causes the thrombus formation. The effect of the TP-receptor antagonist terutroban (S 18886) on different thrombosis models has been evaluated and this has allowed to conclude on the powerful anti-thrombotic effects of this agent and has contributed to its progression into clinical development. In the past the most frequently used model of atherosclerosis was the hypercholesterolemic rabbit; both plaque formation and its consequences on vascular, endothelial, function have been largely studied in this model. More recently genetically engineered mouse models of atherosclerosis have been introduced and they are now largely studied to characterize the disease and to evaluate new drugs. The two models mostly used are the ApoE-/- and the LDL receptor-/- mice. Studies with terutroban have illustrated that this TP-receptor antagonist prevents lesion formation in mouse and rabbit models illustrating its interesting anti-atherosclerotic properties and demonstrating the role played by endothelial TP-receptors in atherogenesis. In conclusion, experimental models to study atherosclerosis and thrombosis have been developed and used to study the etiology and the evolution of atherothrombotic disease. They have also been of great value to predict anti-thrombotic and/or anti-atherosclerotic properties of new substances such as terutroban, that may become novel treatments for this complex cardiovascular disease

Influence of MAO-inhibitors on deamination of 3H-norepinephrine in the dog's saphenous vein

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