Rapid, direct effects of statin treatment on arterial redox state and nitric oxide bioavailability in human atherosclerosis via tetrahydrobiopterin-mediated endothelial nitric oxide synthase coupling.
Rapid, direct effects of statin treatment on arterial redox state and nitric oxide bioavailability in human atherosclerosis via tetrahydrobiopterin-mediated endothelial nitric oxide synthase coupling.
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DOI：
10.1161/circulationaha.110.985150
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发表时间：
2011-07-19
期刊：
影响因子：
37.8
通讯作者：
Channon KM
中科院分区：
文献类型：
--
作者：
Antoniades C;Bakogiannis C;Leeson P;Guzik TJ;Zhang MH;Tousoulis D;Antonopoulos AS;Demosthenous M;Marinou K;Hale A;Paschalis A;Psarros C;Triantafyllou C;Bendall J;Casadei B;Stefanadis C;Channon KM
他汀类药物治疗改善了临床结果，但他汀类多效性药物对人类动脉粥样硬化血管功能的确切作用机制尚不清楚。我们研究了阿托伐他汀对冠心病患者四氢生物蝶呤介导的内皮型一氧化氮合酶偶联的直接影响。我们首先在492例接受冠状动脉搭桥术的患者中研究了他汀类药物治疗与血管NO生物利用度和动脉血氧分压(O2·−)的关系。然后，42例未服用他汀类药物的择期冠状动脉搭桥术患者随机分为阿托伐他汀40 mg/d和安慰剂3天，观察阿托伐他汀对血管内皮功能和乳内动脉O2·−生成的影响。最后，来自26名患者的乳内动脉片段被用于体外实验，以评估他汀类药物依赖的调节血管氧化还原状态的机制。他汀类药物治疗与改善血管NO生物利用度和减少乳内动脉O2·−生成有关。口服阿托伐他汀可增加血管四氢生物蝶呤的生物利用度，降低乳内动脉的基础氧和N-硝基-L-精氨酸甲酯抑制的O2·−，与降低低密度脂蛋白无关。在体外实验中，阿托伐他汀通过上调GTP-环水解酶I基因的表达和活性，迅速提高了血管四氢生物蝶呤的生物利用度，从而改善了血管内皮细胞一氧化氮合酶偶联，降低了血管O2·−。这些作用被甲氧戊酸逆转，表明血管羟甲基戊二酰辅酶A还原酶抑制的直接作用。这项研究首次在人类身上证明了他汀类药物治疗对血管壁的直接影响，支持了这种影响独立于降低低密度脂蛋白的观点。阿托伐他汀通过四氢生物蝶呤介导的内皮一氧化氮合酶偶联，直接改善血管内皮细胞的NO生物利用度，降低血管O2·−。这些发现为他汀类药物对人类有益血管效应的调节机制提供了新的见解。网址：http://www.clinicaltrials.gov.唯一标识：NCT01013103。
Treatment with statins improves clinical outcome, but the exact mechanisms of pleiotropic statin effects on vascular function in human atherosclerosis remain unclear. We examined the direct effects of atorvastatin on tetrahydrobiopterin-mediated endothelial nitric oxide (NO) synthase coupling in patients with coronary artery disease. We first examined the association of statin treatment with vascular NO bioavailability and arterial superoxide (O2·−) in 492 patients undergoing coronary artery bypass graft surgery. Then, 42 statin-naïve patients undergoing elective coronary artery bypass graft surgery were randomized to atorvastatin 40 mg/d or placebo for 3 days before surgery to examine the impact of atorvastatin on endothelial function and O2·− generation in internal mammary arteries. Finally, segments of internal mammary arteries from 26 patients were used in ex vivo experiments to evaluate the statin-dependent mechanisms regulating the vascular redox state. Statin treatment was associated with improved vascular NO bioavailability and reduced O2·− generation in internal mammary arteries. Oral atorvastatin increased vascular tetrahydrobiopterin bioavailability and reduced basal and N-nitro-l-arginine methyl ester–inhibitable O2·− in internal mammary arteries independently of low-density lipoprotein lowering. In ex vivo experiments, atorvastatin rapidly improved vascular tetrahydrobiopterin bioavailability by upregulating GTP-cyclohydrolase I gene expression and activity, resulting in improved endothelial NO synthase coupling and reduced vascular O2·−. These effects were reversed by mevalonate, indicating a direct effect of vascular hydroxymethylglutaryl-coenzyme A reductase inhibition. This study demonstrates for the first time in humans the direct effects of statin treatment on the vascular wall, supporting the notion that this effect is independent of low-density lipoprotein lowering. Atorvastatin directly improves vascular NO bioavailability and reduces vascular O2·− through tetrahydrobiopterin-mediated endothelial NO synthase coupling. These findings provide new insights into the mechanisms mediating the beneficial vascular effects of statins in humans. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01013103.