Shishehbor Mehdi H, Brennan Marie-Luise, Aviles Ronnier J, Fu Xiaoming, Penn Marc S, Sprecher Dennis L, Hazen Stanley L
Department of Cell Biology, and Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic Foundation, 9500 Euclid Ave, NC10, Cleveland, Ohio 44195, USA.
Circulation. 2003 Jul 29;108(4):426-31. doi: 10.1161/01.CIR.0000080895.05158.8B. Epub 2003 Jul 14.
The pleiotropic actions of hydroxymethylglutaryl CoA reductase inhibitors (statins) include antiinflammatory and antioxidant actions. We recently reported that statins induce reductions in plasma protein levels of nitrotyrosine (NO2Tyr), a modification generated by nitric oxide-derived oxidants. Whether alternative oxidative pathways are suppressed in vivo after statin administration has not yet been reported.
As an extension of our prior study, hypercholesterolemic subjects with no known coronary artery disease were evaluated at baseline and after 12 weeks of atorvastatin therapy (10 mg/d). Plasma levels of protein-bound chlorotyrosine, NO2Tyr, dityrosine, and orthotyrosine, specific molecular fingerprints for distinct oxidative pathways upregulated in atheroma, were determined by mass spectrometry. In parallel, alterations in lipoproteins and C-reactive protein were determined. Statin therapy caused significant reductions in chlorotyrosine, NO2Tyr, and dityrosine (30%, 25%, and 32%, respectively; P<0.02 each) that were similar in magnitude to reductions in total cholesterol and apolipoprotein B-100 (25% and 29%, P<0.001 each). Nonsignificant decreases in orthotyrosine and C-reactive protein levels were observed (9% and 11%, respectively; P>0.10 each). Statin-induced reductions in oxidation markers were independent of decreases in lipids and lipoproteins.
Statins promote potent systemic antioxidant effects through suppression of distinct oxidation pathways. The major pathways inhibited include formation of myeloperoxidase-derived and nitric oxide-derived oxidants, species implicated in atherogenesis. The present results suggest potential mechanisms that may contribute to the beneficial actions of statins. They also have important implications for monitoring the antiinflammatory and antioxidant actions of these agents.
羟甲基戊二酰辅酶A还原酶抑制剂（他汀类药物）的多效性作用包括抗炎和抗氧化作用。我们最近报道，他汀类药物可使血浆中硝基酪氨酸（NO2Tyr）的蛋白水平降低，硝基酪氨酸是由一氧化氮衍生的氧化剂产生的一种修饰产物。他汀类药物给药后体内其他氧化途径是否受到抑制尚未见报道。
作为我们先前研究的扩展，对无已知冠状动脉疾病的高胆固醇血症受试者在基线时以及阿托伐他汀治疗（10mg/d）12周后进行评估。通过质谱法测定血浆中与蛋白结合的氯酪氨酸、NO2Tyr、二酪氨酸和邻酪氨酸水平，这些是动脉粥样硬化中上调的不同氧化途径的特定分子指纹。同时，测定脂蛋白和C反应蛋白的变化。他汀类药物治疗导致氯酪氨酸、NO2Tyr和二酪氨酸显著降低（分别降低30%、25%和32%；P均<0.02），其降低幅度与总胆固醇和载脂蛋白B-100的降低幅度相似（分别降低25%和29%，P均<0.001）。观察到邻酪氨酸和C反应蛋白水平有非显著性下降（分别下降9%和11%；P均>0.10）。他汀类药物诱导的氧化标志物降低与脂质和脂蛋白的降低无关。
他汀类药物通过抑制不同的氧化途径发挥强大的全身抗氧化作用。所抑制的主要途径包括髓过氧化物酶衍生的氧化剂和一氧化氮衍生的氧化剂的形成，这些物质与动脉粥样硬化的发生有关。目前的结果提示了可能有助于他汀类药物有益作用的潜在机制。它们对于监测这些药物的抗炎和抗氧化作用也具有重要意义。
