This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 29/7/1039    most recent ATVBAHA.109.185405v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Zhu, L. Articles by Brass, L. F. PubMed PubMed Citation Articles by Zhu, L. Articles by Brass, L. F.

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1039.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Disruption of SEMA4D Ameliorates Platelet Hypersensitivity in Dyslipidemia and Confers Protection Against the Development of Atherosclerosis

Li Zhu; Timothy J. Stalker; Karen P. Fong; Hong Jiang; Anh Tran; Irene Crichton; Eric K. Lee; Keith B. Neeves; Sean F. Maloney; Hitoshi Kikutani; Atsushi Kumanogoh; Ellen Pure; Scott L. Diamond; Lawrence F. Brass

From the Departments of Medicine and Pharmacology (L.Z., T.J.S., K.P.F., H.J., A.T., L.F.B.) and Chemical Engineering (K.B.N., S.F.M., S.L.D.), University of Pennsylvania, and the Wistar Institute (I.C., E.K.L., E.P.), Philadelphia, Pa; and the Departments of Immunopathology and Molecular Immunology (H.K., A.K.), Research Institute for Microbial Diseases, Osaka University, Japan. Current address for K.B.N.: Chemical Engineering, Colorado School of Mines, Golden.

Correspondence to Lawrence F. Brass, MD, PhD, University of Pennsylvania, 915 BRB II/III, 421 Curie Blvd, Philadelphia, PA 19104. E-mail brass{at}mail.med.upenn.edu

Objective— In dyslipidemic states, platelets become hyperreactive, secreting molecules that promote atherosclerosis. We have shown that the semaphorin family member, sema4D (CD100), is expressed on the surface of platelets and proposed that its role includes promoting thrombus growth by binding to nearby platelets and endothelial cells, both of which express sema4D receptors. Here we tested the hypothesis that deleting sema4D will attenuate the adverse consequences of dyslipidemia on platelets and the vessel wall.

Methods and Results— Platelet function and atherosclerotic lesion formation were measured in LDLR(–/–) and sema4D(–/–)LDLR(–/–) mice after 6 months on a high-fat diet. All of the mice developed the dyslipidemia expected on this diet in the absence of functional LDL receptors. However, when compared to LDLR(–/–) mice, sema4D(–/–) LDLR(–/–) mice had reduced lipid deposition in the descending aorta, a 6-fold decrease in the frequency of arterial occlusion and a reduction to near wild-type levels in the accumulation of platelets after injury. These differences were retained ex vivo, with a marked decrease in platelet accumulation on collagen under flow and in platelet aggregation.

Conclusions— These results show that loss of sema4D expression reduces the platelet hyperactivity otherwise found in dyslipidemia, and confers protection against the development of atherosclerosis.

We previously demonstrated that semaphorin-4D modulates platelet function. Here, we examined the role of Sema4D in platelet function and atherogenesis in dyslipidemia. Deletion of Sema4D ameliorated atherosclerotic plaque formation and platelet hyperreactivity in dyslipidemic mice. These findings suggest that sema4D and its receptors provide a new target mechanism for preventing the development of atherothrombotic disease.

Key Words: semaphorin 4D • atherosclerosis • platelet • dyslipidemia