BM-573 inhibits the development of early atherosclerotic lesions in Apo E deficient mice by blocking TP receptors and thromboxane synthase

• Published in: Prostaglandins & other lipid mediators Vol. 94; no. 3; pp. 124 - 132
• Main Authors: Cherdon, Céline, Rolin, Stéphanie, Hanson, Julien, Ooms, Annie, de Leval, Laurence, Drion, Pierre, Michiels, Carine, Pirotte, Bernard, Masereel, Bernard, Sakalihassan, Natzi, Defraigne, Jean-Olivier, Dogné, Jean-Michel
• Format: Journal Article Web Resource
• Language: English
• Published: United States Elsevier Inc 01.04.2011; Elsevier Science
• Subjects: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid - metabolism; adhesion molecule; Animals; Apolipoproteins E - genetics; aspirin; Aspirin - therapeutic use; Atherosclerosis; Atherosclerosis - prevention & control; BM-573; Cardiovascular & respiratory systems; cyclooxygenase; Dinoprost - analogs & derivatives; Dinoprost - metabolism; Drug Therapy, Combination; Endothelial cells; Endothelial Cells - cytology; Human health sciences; Humans; Intercellular Adhesion Molecule-1 - metabolism; isoprostane; Mice; Mice, Knockout; Receptors, Thromboxane - antagonists & inhibitors; Saphenous Vein - cytology; Sciences de la santé humaine; Sulfonylurea Compounds - therapeutic use; Systèmes cardiovasculaire & respiratoire; Thromboxane; Thromboxane A2 - antagonists & inhibitors; Thromboxane A2 - biosynthesis; Thromboxane B2 - antagonists & inhibitors; Thromboxane B2 - biosynthesis; Thromboxane-A Synthase - antagonists & inhibitors; TP receptor; Vascular Cell Adhesion Molecule-1 - metabolism; TP receptor; Thromboxane; Endothelial cells; Atherosclerosis
• ISSN: 1098-8823
• DOI: 10.1016/j.prostaglandins.2011.03.001

► BM-573 significantly decreases atherogenesis lesions in apo E deficient mice. ► BM-573 is more effective than ASA alone in reducing atherogenesis. ► The effects of BM-573 on atherosclerosis may be explained by a reduction of ICAM-1 and VCAM-1. ► In HSVECs, BM-573 prevented expression of ICAM-1 and VCAM-1 induced by U-46619 and 8-iso-PGF 2α. 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.