Antithrombotic and antiplatelet activities of fenofibrate, a lipid-lowering drug

Abstract

Fenofibrate, a lipid-lowering drug, inhibits hydroxyl-methylglutaryl coenzyme A (HMG-CoA)-reductase activity, thus reducing cholesterol synthesis and increasing the clearance of circulating LDL-cholesterol via the high affinity receptor system. In addition, fenofibrate has beneficial effects such as the inhibition of tissue factor expression, antithrombotic effect and anti-inflammatory effect. The aim of this study was to investigate the effects of fenofibrate on thrombus formation in vivo and platelet activation in vitro and ex vivo. The carotid arteries of male Sprague-Dawley rats were subjected to chemical injury by FeCl3, and then blood flow was measured with a blood flowmeter. Fenofibrate (200 and 400 mg/kg/day for 1 week) delayed the time to occlusion by 61.3% (p < 0.05, n = 10) and 90.7% (p < 0.01, n = 10), respectively. Fenofibrate also significantly inhibited ex vivo platelet aggregations induced by collagen (7.5 mu g/ml) (p < 0.01, n = 11) and ADP (10 mu M) (p < 0.01, n = 11), respectively, but did not affect coagulation times following activated partial thromboplastin and prothrombin activation, indicating the antithrombotic effect was mediated by its inhibition on platelet activation rather than coagulation system. This antiplatelet activity was revealed to be mediated by the suppression of thromboxane A(2) receptor, cytosolic calcium mobilization, and cyclooxygenase (COX)-1 activity. Taken together, we demonstrate that fenofibrate can significantly inhibit artery thrombus formation in vivo, which may be due to antiplatelet activity via the inhibition of thromboxane A(2) receptor, cytosolic calcium mobilization and COX-1 activity, and the beneficial effect of fenofibrate on cardiovascular system may be also due to its modulation of platelet activation. (C) 2009 Elsevier Ireland Ltd. All rights reserved.