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(Circulation. 2005;112:3001-3008.)
© 2005 American Heart Association, Inc.

Vascular Medicine

The Thromboxane A₂ Receptor Antagonist S18886 Prevents Enhanced Atherogenesis Caused by Diabetes Mellitus

Adriana Zuccollo, PhD; Chaomei Shi, MD; Roberto Mastroianni, BA; Karlene A. Maitland-Toolan, BS; Robert M. Weisbrod, MA; Mengwei Zang, MD, PhD; Shanqin Xu, MS, MD; Bingbing Jiang, MD, PhD; Jennifer M. Oliver-Krasinski, AB; Antonio J. Cayatte, MD; Stefano Corda, MD, PhD; Gilbert Lavielle, PhD; Tony J. Verbeuren, PhD; Richard A. Cohen, MD

From the Vascular Biology Unit, Department of Medicine, Boston University School of Medicine, Boston, Mass (A.Z., C.S., R.M., K.A.M.-T., R.M.W., M.Z., S.X., B.J., J.M.O.-K., A.J.C., R.A.C.); Institut de Recherches Internationales Servier, Courbevoie, France (S.C.); Division of Chemistry, Institut de Recherches Servier, Croissy, France (G.L.); and Division of Angiology, Institut de Recherches Servier, Suresnes, France (T.J.V.).

Correspondence to Richard A. Cohen, MD, Vascular Biology Unit, X704 Boston University Medical Center, 650 Albany St, Boston, MA 02118. E-mail racohen{at}bu.edu

Received May 4, 2005; de novo received August 9, 2005; accepted August 25, 2005.

Background— S18886 is an orally active thromboxane A₂ (TXA₂) receptor (TP) antagonist in clinical development for use in secondary prevention of thrombotic events in cardiovascular disease. We previously showed that S18886 inhibits atherosclerosis in apolipoprotein E–deficient (apoE^–/–) mice by a mechanism independent of platelet-derived TXA₂. Atherosclerosis is accelerated by diabetes and is associated with increased TXA₂ and other eicosanoids that stimulate TP. The purpose of this study was to determine whether S18886 lessens the enhanced atherogenesis in diabetic apoE^–/– mice.

Methods and Results— Diabetes mellitus was induced in apoE^–/– mice with streptozotocin and was treated or not with S18886 (5 mg · kg^–1 · d^–1). After 6 weeks, aortic lesion area was increased >4-fold by diabetes in apoE^–/– mice, associated with similar increases in serum glucose and cholesterol. S18886 largely prevented the diabetes-related increase in lesion area without affecting the hyperglycemia or hypercholesterolemia. S18886 prevented deterioration of endothelial function and endothelial nitric oxide synthase expression, as well as increases in intimal markers of inflammation associated with diabetes. In human aortic endothelial cells in culture, S18886 also prevented the induction of vascular cell adhesion molecule-1 and prevented the decrease in endothelial nitric oxide synthase expression caused by high glucose.

Conclusions— The TP antagonist inhibits inflammation and accelerated atherogenesis caused by diabetes, most likely by counteracting effects on endothelial function and adhesion molecule expression of eicosanoids stimulated by the diabetic milieu.

Key Words: atherosclerosis • diabetes mellitus • inflammation • nitric oxide synthase • thromboxane

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