title: Effects of the dual TP receptor antagonist and thromboxane synthase inhibitor EV-077 on human endothelial and vascular smooth muscle cells.
abstract: The prothrombotic mediator thromboxane A2 is derived from arachidonic acid metabolism through the cyclooxygenase and thromboxane synthase pathways, and transduces its effect through the thromboxane prostanoid (TP) receptor. The aim of this study was to determine the effect of the TP receptor antagonist and thromboxane synthase inhibitor EV-077 on inflammatory markers in human umbilical vein endothelial cells and on human coronary artery smooth muscle cell proliferation. To this end, mRNA levels of different proinflammatory mediators were studied by real time quantitative PCR, supernatants were analyzed by enzyme immune assay, and cell proliferation was assessed using WST-1. EV-077 significantly decreased mRNA levels of ICAM-1 and PTX3 after TNFα incubation, whereas concentrations of 6-keto PGF1α in supernatants of endothelial cells incubated with TNFα were significantly increased after EV-077 treatment. Although U46619 did not alter coronary artery smooth muscle cell proliferation, this thromboxane mimetic enhanced the proliferation induced by serum, insulin and growth factors, which was significantly inhibited by EV-077. In conclusion, EV-077 inhibited TNFα-induced endothelial inflammation and reduced the enhancement of smooth muscle cell proliferation induced by a thromboxane mimetic, supporting that the thromboxane pathway may be associated with early atherosclerosis in terms of endothelial dysfunction and vascular hypertrophy.
authors.affiliation: Department of Medicine, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Marcelo H
authors.initials: MH
authors.lastname: Petri
authors.forename: Céline
authors.initials: C
authors.lastname: Tellier
authors.forename: Carine
authors.initials: C
authors.lastname: Michiels
authors.forename: Ingvill
authors.initials: I
authors.lastname: Ellertsen
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Dogné
authors.forename: Magnus
authors.initials: M
authors.lastname: Bäck
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D002097:C-Reactive Protein / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D011460:Prostaglandins F / Q000378:metabolism; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D000683:Serum Amyloid P-Component / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D013928:Thromboxane A2 / Q000502:physiology; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000099153:Pentraxins
chemical_list: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D002097:C-Reactive Protein; D018799:Intercellular Adhesion Molecule-1; D011460:Prostaglandins F; D012333:RNA, Messenger; D017482:Receptors, Thromboxane; D000683:Serum Amyloid P-Component; D013928:Thromboxane A2; D013930:Thromboxane-A Synthase; D014409:Tumor Necrosis Factor-alpha; D000099153:Pentraxins; C573420:ICAM1 protein, human; C100006:prostaglandin F1
keywords: Eicosanoids; Endothelial cells; Inflammation; Smooth muscle cells; Thromboxane prostanoid receptor