Anti-thrombotic Effects of Atorvastatin-An Effect Unrelated to Lipid Lowering

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Abstract
Statins (3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) have been shown to reduce clinical events in excess of what can be explained by altering lipid profile. Statins have been shown to possess modest antioxidant and antiplatelet aggregatory effect. We postulated that statins may accordingly inhibit arterial thrombus formation. To assess the antithrombotic effects of atorvastatin, a commonly used statin, in response to an oxidant stimulus, we fed Sprague-Dawley rats either regular chow, or chow mixed with atorvastatin (1.25 mg/kg) for 10 days (n = 16 in each group). Eight rats in each group were also given oxidized low-density lipoprotein intravenously prior to the induction of thrombus. An occlusive thrombus was created in the abdominal aorta by application of Whatman paper soaked in 35% FeCl3. The time to occlusive thrombus formation was not altered by administration of oxidized low-density lipoprotein in the rats fed regular chow or chow mixed with atorvastatin. However, time to thrombosis was increased in the group given chow mixed with atorvastatin (26 ± 4 minutes vs. 20 ± 5 minutes, P < 0.02). To determine the mechanism of atorvastatin's antithrombotic effect, we measured the expression of endothelial constitutive nitric oxide synthase (cNOS) in rat aortas by Western analysis. The cNOS protein expression was enhanced 75% in rats fed chow with atorvastatin (P < 0.01 vs. rats fed regular chow). Plasma levels of total cholesterol and low-density lipoprotein-cholesterol were similar in all groups. This study shows that atorvastatin delays thrombus formation in arterial channels exposed to oxidant stress. This effect of atorvastatin appears to be related to increased expression of cNOS, which is known to inhibit platelet aggregation and induce vasodilatation. The effects of atorvastatin are independent of its effects on plasma cholesterol levels.