Hussein O, Schlezinger S, Rosenblat M, Keidar S, Aviram M
Lipid Research Laboratory, Rambam Medical Center, Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.
Atherosclerosis. 1997 Jan 3;128(1):11-8. doi: 10.1016/s0021-9150(96)05972-2.
Increased plasma cholesterol concentration in hypercholesterolemic patients is a major risk factor for atherosclerosis. The impaired removal of plasma low density lipoprotein (LDL) in these patients results in the presence of their LDL in the plasma for a long period of time and thus can contribute to its enhanced oxidative modification. In the present study we analyzed the effect of the hypocholesterolemic drug, fluvastatin, on plasma and LDL susceptibilities to oxidation during 24 weeks of therapy. Fluvastatin therapy (40 mg/day for 24 weeks) in 10 hypercholesterolemic patients resulted in 30%, 34% and 22% decrements in plasma levels of total cholesterol, LDL cholesterol and triglycerides, respectively. This effect has been achieved after only 4 weeks of therapy. We next studied the effect of fluvastatin therapy on LDL susceptibility to oxidation in vivo and in vitro. 2.2-Azobis, 2-amidinopropane hydrochloride (AAPH, 100 mM)-induced plasma lipid peroxidation was decreased by 70% and 77% after 12 weeks and 24 weeks of fluvastatin therapy respectively. The lag time required for the initiation of CuSO4 (10 microM)-induced LDL oxidation was prolonged by 1.2- and 2.5-fold, after 12 and 24 weeks of fluvastatin therapy respectively. We next analyzed the in vitro effect of fluvastatin on plasma and LDL susceptibilities to oxidation. Preincubation of plasma or LDLs that were obtained from normal subjects with 0.1 microgram/ml of fluvastatin, caused 20% or 57% reduction in AAPH-induced lipid peroxidation, respectively. Similarly, a 1.6- and 2.7-fold prolongation of the lag time required for CuSO4-induced LDL oxidation was found following LDL incubation with 0.1 and 1.0 microgram/ml of fluvastatin, respectively. To find out possible mechanisms that contribute to this inhibitory effect of fluvastatin on LDL oxidizability, we analyzed the antioxidative properties of fluvastatin. Fluvastatin did not scavenge free radicals and did not inhibit linoleic acid peroxidation. Fluvastatin also did not act as a chelator of copper ions. However, fluvastatin was shown to specifically bind mainly to the LDL surface phospholipids and this interaction altered the lipoprotein charge as evident from the 38% decrement in the electrophoretic mobility of fluvastatin-treated LDL, in comparison to nontreated LDL. The inhibitory effect of fluvastatin therapy on LDL oxidation probably involves both its stimulatory effect on LDL removal from the circulation, as well as a direct binding effect of the drug to the lipoprotein. We thus conclude that the antiatherogenic properties of fluvastatin may not be limited to its hypocholesterolemic effect, but could also be related to its ability to reduce LDL oxidizability.
高胆固醇血症患者血浆胆固醇浓度升高是动脉粥样硬化的主要危险因素。这些患者血浆低密度脂蛋白（LDL）清除受损，导致其LDL在血浆中长时间存在，从而可能导致其氧化修饰增强。在本研究中，我们分析了降胆固醇药物氟伐他汀在24周治疗期间对血浆和LDL氧化敏感性的影响。10名高胆固醇血症患者接受氟伐他汀治疗（40mg/天，共24周）后，血浆总胆固醇、LDL胆固醇和甘油三酯水平分别下降了30%、34%和22%。仅在治疗4周后就达到了这一效果。接下来，我们研究了氟伐他汀治疗对体内和体外LDL氧化敏感性的影响。氟伐他汀治疗12周和24周后，2,2-偶氮二（2-脒基丙烷）二盐酸盐（AAPH，100mM）诱导的血浆脂质过氧化分别降低了70%和77%。氟伐他汀治疗12周和24周后，CuSO4（10μM）诱导的LDL氧化起始所需的延迟时间分别延长了1.2倍和2.5倍。接下来，我们分析了氟伐他汀对血浆和LDL氧化敏感性的体外影响。用0.1μg/ml氟伐他汀预孵育从正常受试者获得的血浆或LDL，分别使AAPH诱导的脂质过氧化降低了20%或57%。同样，LDL与0.1μg/ml和1.0μg/ml氟伐他汀孵育后，CuSO4诱导的LDL氧化所需的延迟时间分别延长了1.6倍和2.7倍。为了找出氟伐他汀对LDL氧化抑制作用的可能机制，我们分析了氟伐他汀的抗氧化特性。氟伐他汀不清除自由基，也不抑制亚油酸过氧化。氟伐他汀也不充当铜离子的螯合剂。然而，已证明氟伐他汀主要特异性结合到LDL表面磷脂上，这种相互作用改变了脂蛋白电荷，与未处理的LDL相比，氟伐他汀处理的LDL电泳迁移率降低了38%，这一点很明显。氟伐他汀治疗对LDL氧化的抑制作用可能涉及其对循环中LDL清除的刺激作用，以及药物与脂蛋白的直接结合作用。因此，我们得出结论，氟伐他汀的抗动脉粥样硬化特性可能不仅限于其降胆固醇作用，还可能与其降低LDL氧化能力有关。
