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(Circulation. 2001;103:1135.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Effect of Selective or Combined Inhibition of Integrins _IIbß₃ and _vß₃ on Thrombosis and Neointima After Oversized Porcine Coronary Angioplasty

Timothy J. A. Chico, MRCP; Janet Chamberlain, PhD; Julian Gunn, MD; Nadine Arnold, VN; Sherron L. Bullens, AB; Thomas R. Gadek, PhD; Sheila E. Francis, PhD; Stuart Bunting, PhD; Michael Horton, PhD; Lynda Shepherd; Michael T. Lipari, MSc; Clifford Quan, PhD; Jochen Knolle, PhD; Hans Ulrich Stilz, PhD; Anusch Peyman, PhD; David C. Crossman, MD

From the Cardiovascular Research Group, Division of Clinical Sciences (NGHT), University of Sheffield, Clinical Sciences Centre, Northern General Hospital, Sheffield, UK (T.J.A.C., J.C., J.G., N.A., S.E.F., L.S., D.C.C.); Genentech Inc, South San Francisco, Calif (S.L.B., T.R.G., S.B., M.T.L., C.Q.); the Department of Medicine, University College London Medical School, UK (M.H.); and Hoechst Marion Roussel Deutschland GmbH, Frankfurt, Germany (J.K., H.U.S., A.P.).

Correspondence to Timothy J.A. Chico, MRCP, Cardiovascular Research, Genentech Inc, 1 DNA Way, South San Francisco, CA 94080. E-mail timchico{at}gene.com

Background—Thrombosis and neointima formation limit the efficacy of coronary angioplasty (PTCA). Clinical trials have implicated the adhesion molecules integrin _IIbß₃ and integrin _vß₃ in these processes. The roles of these molecules in vascular smooth muscle cell adhesion, platelet aggregation, and the thrombotic and neointimal response to oversize porcine PTCA was investigated by use of a selective _IIbß₃ antagonist (lamifiban), a selective _vß₃ antagonist (VO514), and a combined _IIbß₃/_vß₃ antagonist (G3580).

Methods and Results—In vitro, both _vß₃ inhibitors caused dose-dependent inhibition of porcine vascular smooth muscle cell adhesion to vitronectin but not to collagen type IV, fibronectin, or laminin, whereas selective _IIbß₃ inhibition had no effect. Intravenous infusions of either _IIbß₃ inhibitor in swine profoundly inhibited ex vivo platelet aggregation to ADP, whereas selective _vß₃ inhibition had no effect. In a porcine PTCA model, intravenous infusions of the integrin antagonists were administered for 14 days after oversized balloon angioplasty injury. After PTCA, there was regional upregulation of integrin _vß₃ in the developing neointima, as assessed by immunohistochemistry. Six hours after PTCA, obstruction of lumen by thrombus was reduced significantly by _IIbß₃ inhibition compared with either control or _vß₃ inhibition (mean control, 18.7%; VO514, 18.5%; lamifiban, 6.4%; G3580, 7.9%). Twenty-eight days after PTCA, there was a significant reduction of neointima with inhibitors of either integrin (mean intima/media ratio: control, 3.08; VO514, 1.33; lamifiban, 0.97; G3580, 1.32).

Conclusions—We conclude that both integrin _IIbß₃ and integrin _vß₃ participate in neointima development after experimental angioplasty.

Key Words: platelets • cell adhesion molecules • angioplasty • thrombosis

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