Fluvastatin ameliorates the hyperhomocysteinemia-induced endothelial dysfunction - The antioxidative properties of fluvastatin
Fluvastatin ameliorates the hyperhomocysteinemia-induced endothelial dysfunction - The antioxidative properties of fluvastatin
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DOI：
10.1253/circj.69.475
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发表时间：
2005-04-01
影响因子：
3.3
通讯作者：
Nagai, R
中科院分区：
文献类型：
--
作者：
Morita, H;Saito, Y;Nagai, R
高同型半胱氨酸血症可诱导血管内皮功能障碍，促进动脉粥样硬化的发生和/或进展。同型半胱氨酸对血管功能的不利影响的主要机制似乎涉及氧化应激。因此，我们假设，3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂氟伐他汀，这是实验证明具有抗氧化特性作为其多效性的影响之一，是一个有用的策略，用于消除有害事件引起的hyperhomocysteinemia.Methods和Results在饮食诱导的hyperhomocysteinemia大鼠，我们估计氧化应激和评估内皮依赖性血管舒张。高同型半胱氨酸血症诱导尿8-异前列腺素F2 α-III排泄和血管超氧化物生成显著增加，内皮依赖性血管舒张受损。额外的口服抗氧化剂氟伐他汀或维生素E，正常化高同型半胱氨酸血症引起的氧化应激增加，改善内皮功能障碍。结论高同型半胱氨酸血症，即使是轻度至中度，通过其氧化作用诱导内皮功能障碍。抗氧化剂氟伐他汀能够消除高同型半胱氨酸血症引起的氧化应激，改善内皮功能障碍。氟伐他汀的临床应用可能是消除高同型半胱氨酸血症和高脂血症引起的不良事件的有效策略。除了通过补充叶酸降低同型半胱氨酸外，抗氧化剂的给药有望成为一种潜在有效的抗同型半胱氨酸疗法。
Background Hyperhomocysteinemia induces vascular endothelial dysfunction, contributing to a predisposition to the onset and/or progression of atherosclerosis. The major mechanism suggested for the adverse effect of homocysteine on vascular function seems to involve oxidative stress. Thus, we hypothesized that the administration of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor fluvastatin, which is experimentally demonstrated to have antioxidative properties as one of its pleiotropic effects, is a useful strategy for eliminating the detrimental events induced by hyperhomocysteinemia.Methods and Results In diet-induced hyperhomocysteinemic rats, we estimated oxidative stress and assessed endothelium-dependent vasodilatation. Hyperhomocysteinemia induced significant increases in urinary 8-isoprostaglandin F2 alpha-III excretion and vascular superoxide generation, and impaired endothelium-dependent vasodilatation. Additional oral administration of the antioxidant fluvastatin or vitamin E, which normalized increased oxidative stress induced by hyperhomocysteinemia, ameliorated endothelial dysfunction.Conclusions Hyperhomocysteinemia, even mild to moderate, induces endothelial dysfunction through its oxidative effect. The antioxidant fluvastatin was able to cancel out the oxidative stress induced by hyperhomocysteinemia and ameliorate endothelial dysfunction. Clinical use of fluvastatin might be a potent strategy for eliminating the detrimental events induced by hyperhomocysteinemia as well as hyperlipidemia. In addition to lowering homocysteine by means of folate supplementation, administration of the antioxidants is expected to be a potentially effective anti-homocysteine therapy.