Prevention of neointimal formation by a serine protease inhibitor, FUT-175, after carotid balloon injury in rats

Background and Purpose-In vivo and vitro studies revealed the activation of thrombin and the complement system in vascular lesion formation during the process of atherosclerosis, along with pathological proliferation of smoot h muscle cells. We examined the effect of the synthetic serine protease inh ibitor FUT-175 (developed as a potent inhibitor of thrombin and the complem ent system) on vascular lesions using balloon dilatation-induced neointimal formation in the carotid artery of rats. Methods-Sprague-Dawley (SD) rats underwent balloon dilatation injury of the left carotid artery to induce neointimal formation. Three groups of these rats (n=8, each) were treated with daily intraperitoneal injections of 1 of the following doses of FUT-175: 0.5, 1.0, or 2.0 mg/d in 1 mt of saline fo r 7 consecutive days. The control group (n = 8) was similarly treated with 1 mi, of saline for 7 days. The injections were started immediately after b alloon injury. Two weeks after the injury, the left carotid arteries were p erfusion-fixed, and the areas of the neointimal and medial layer were analy zed under a microscope. Results-A morphometric analysis revealed that there were significant differ ences in the intima-media ratio between the 4 groups treated with vehicle ( saline) or a low, medium, or high dose of FUT-175 (1.45+/-0.11, 1.08+/-0.06 , 0.71+/-0.04, or 0.32+/-0.04, respectively). This suppression was achieved in a dose-dependent manner by the administration of FUT-175 after balloon injury. In the histological study, it was demonstrated that FUT-175 suppres ses the production of platelet-derived growth factor (PDGF)-BB in the neoin tima and the medial smooth muscle cell layer. Conclusions-After balloon injury activated proteases that were inhibited by FUT-175 were demonstrated to have an essential role in the development of the pathological thickening of the arterial wall.