Mechanisms involved in the inhibition of neointimal hyperplasia by abciximab in a rat model of balloon angioplasty

Monoclonal antibodies raised against beta (3) integrin are able to inhibit the binding of ligands to certain beta (3) integrins such as alpha (IIb)bet a (3) (glycoprotein IIb/IIIa complex) and alpha (v)beta (3) (vitronectin re ceptor) and as such are inhibitors of platelet aggregation and smooth muscl e cell (SMC) migration, both of which are involved in neointimal hyperplasi a. The present study was designed to explore the detailed mechanisms of abc iximab (Reopro), a monoclonal antibody (mAb) raised against alpha (IIb)beta (3) integrin in neointimal hyperplasia. In this study, carotid arteries of Wistar rats were damaged, and neointimal hyperplasia and lumen occlusion w as determined at different time points. Abciximab was administered intraven ously by an implanted osmotic pump. Abciximab (0.25 mg/kg/day) time-depende ntly inhibited both neointimal hyperplasia and lumen occlusion after angiop lasty in carotid arteries of rats. Furthermore, the electromicrographs high lighted that SMCs were phenotypically different from the typical contractil e, spindle-shaped SMCs normally seen in uninjured vessel walls. Platelet-de rived growth factor (PDGF)-BB was strongly produced in thrombus formation a nd neointimal SMCs after angioplasty, while abciximab significantly reduced PDGF-BB expression in vessel lumens and neointimal SMCs after angioplasty. Balloon angioplasty caused a significant increase of nitrate and cyclic GM P as compared with sham-operated rats. Infusion of abciximab (0.25 mg/ kg/d ay) did not significantly change. Furthermore, the plasma level of thrombox ane B-2 (TxB(2)) obviously increased after angioplasty, while abciximab mar kedly suppressed the elevation of plasma TxB(2) concentration. The results indicate that abciximab effectively prevents neointimal hyperplasia, possib ly through the following 2 mechanisms: (1) Abciximab binds to alpha (IIb)be ta (3) integrin on platelet membranes resulting in inhibition of platelet a dhesion, secretion, and aggregation in injured arteries, followed by inhibi tion of thromboxane A(2) formation and PDGF-BB release from platelets. (2) Abciximab may also bind to alpha (v)beta (3) integrin on SMCs, thus, subseq uently inhibiting cell migration and proliferation. (C) 2001 Elsevier Scien ce Ltd. All rights reserved.