Wu C H, Chen Y C, Hsiao G, Lin C H, Liu C M, Sheu J R
Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan, ROC.
Thromb Res. 2001 Feb 1;101(3):127-38. doi: 10.1016/s0049-3848(00)00384-4.
Monoclonal antibodies raised against beta(3) integrin are able to inhibit the binding of ligands to certain beta(3) integrins such as alpha(IIb)beta(3) (glycoprotein IIb/IIIa complex) and alpha(v)beta(3) (vitronectin receptor) and as such are inhibitors of platelet aggregation and smooth muscle cell (SMC) migration, both of which are involved in neointimal hyperplasia. The present study was designed to explore the detailed mechanisms of abciximab (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 was determined at different time points. Abciximab was administered intravenously by an implanted osmotic pump. Abciximab (0.25 mg/kg/day) time-dependently inhibited both neointimal hyperplasia and lumen occlusion after angioplasty in carotid arteries of rats. Furthermore, the electromicrographs highlighted that SMCs were phenotypically different from the typical contractile, spindle-shaped SMCs normally seen in uninjured vessel walls. Platelet-derived growth factor (PDGF)-BB was strongly produced in thrombus formation and 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 GMP as compared with sham-operated rats. Infusion of abciximab (0.25 mg/kg/day) did not significantly change. Furthermore, the plasma level of thromboxane B(2) (TxB(2)) obviously increased after angioplasty, while abciximab markedly suppressed the elevation of plasma TxB(2) concentration. The results indicate that abciximab effectively prevents neointimal hyperplasia, possibly through the following 2 mechanisms: (1) Abciximab binds to alpha(IIb)beta(3) integrin on platelet membranes resulting in inhibition of platelet adhesion, secretion, and aggregation in injured arteries, followed by inhibition 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, subsequently inhibiting cell migration and proliferation.
针对β(3)整合素产生的单克隆抗体能够抑制配体与某些β(3)整合素的结合，如α(IIb)β(3)（糖蛋白IIb/IIIa复合物）和α(v)β(3)（玻连蛋白受体），因此是血小板聚集和平滑肌细胞（SMC）迁移的抑制剂，而这两者均参与了内膜增生。本研究旨在探究阿昔单抗（Reopro），一种针对α(IIb)β(3)整合素产生的单克隆抗体（mAb）在抑制内膜增生方面的详细机制。在本研究中，Wistar大鼠的颈动脉受到损伤，并在不同时间点测定内膜增生和管腔闭塞情况。通过植入渗透泵静脉注射阿昔单抗。阿昔单抗（0.25mg/kg/天）能时间依赖性地抑制大鼠颈动脉血管成形术后的内膜增生和管腔闭塞。此外，电子显微镜照片显示，平滑肌细胞的表型与未受损血管壁中常见的典型收缩性、梭形平滑肌细胞不同。血管成形术后，血小板衍生生长因子（PDGF）-BB在血栓形成和内膜平滑肌细胞中大量产生，而阿昔单抗能显著降低血管成形术后血管腔和内膜平滑肌细胞中PDGF-BB的表达。与假手术大鼠相比，球囊血管成形术导致硝酸盐和环磷酸鸟苷显著增加。输注阿昔单抗（0.25mg/kg/天）并没有显著改变。此外，血管成形术后血栓素B(2)（TxB(2)）的血浆水平明显升高，而阿昔单抗显著抑制了血浆TxB(2)浓度的升高。结果表明，阿昔单抗可能通过以下两种机制有效预防内膜增生：（1）阿昔单抗与血小板膜上的α(IIb)β(3)整合素结合，导致受损动脉中血小板的黏附、分泌和聚集受到抑制，随后抑制血栓素A(2)的形成以及血小板释放PDGF-BB。（2）阿昔单抗也可能与平滑肌细胞上的α(v)β(3)整合素结合，从而随后抑制细胞迁移和增殖。
