Gaddam V, Li D Y, Mehta J L
Division of Cardiovascular Medicine, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA.
J Cardiovasc Pharmacol Ther. 2002 Oct;7(4):247-53. doi: 10.1177/107424840200700408.
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.
他汀类药物（3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂）已被证明可减少临床事件，其作用超出了通过改变血脂水平所能解释的范围。他汀类药物已被证明具有适度的抗氧化和抗血小板聚集作用。我们推测他汀类药物可能因此抑制动脉血栓形成。为了评估常用的他汀类药物阿托伐他汀在应对氧化应激刺激时的抗血栓作用，我们给Sprague-Dawley大鼠喂食普通饲料或与阿托伐他汀（1.25毫克/千克）混合的饲料，持续10天（每组n = 16）。每组中的8只大鼠在诱导血栓形成前还静脉注射了氧化型低密度脂蛋白。通过应用浸泡在35%三氯化铁中的Whatman滤纸在腹主动脉中形成闭塞性血栓。在喂食普通饲料或与阿托伐他汀混合饲料的大鼠中，氧化型低密度脂蛋白的给药并未改变闭塞性血栓形成的时间。然而，给予与阿托伐他汀混合饲料的组血栓形成时间增加（26±4分钟对20±5分钟，P < 0.02）。为了确定阿托伐他汀抗血栓作用的机制，我们通过蛋白质免疫印迹分析测量了大鼠主动脉中内皮型一氧化氮合酶（cNOS）的表达。喂食含阿托伐他汀饲料的大鼠中cNOS蛋白表达增强了75%（与喂食普通饲料的大鼠相比，P < 0.01）。所有组的总胆固醇和低密度脂蛋白胆固醇血浆水平相似。这项研究表明，阿托伐他汀可延迟暴露于氧化应激的动脉通道中的血栓形成。阿托伐他汀的这种作用似乎与cNOS表达增加有关，已知cNOS可抑制血小板聚集并诱导血管舒张。阿托伐他汀的作用与其对血浆胆固醇水平的影响无关。
