Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital OX3 9DU, Oxford, UK.
Circulation. 2011 Jul 19;124(3):335-45. doi: 10.1161/CIRCULATIONAHA.110.985150. Epub 2011 Jul 5.
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 (O(2)(·-)) 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 O(2)(·-) 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 O(2)(·-) generation in internal mammary arteries. Oral atorvastatin increased vascular tetrahydrobiopterin bioavailability and reduced basal and N-nitro-l-arginine methyl ester-inhibitable O(2)(·-) 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 O(2)(·-). 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 O(2)(·-) 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.
他汀类药物治疗可改善临床预后，但他汀类药物对人类动脉粥样硬化血管功能的多效性作用的确切机制仍不清楚。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作用。
我们首先在 492 例行冠状动脉旁路移植术的患者中研究了他汀类药物治疗与血管一氧化氮生物利用度和动脉超氧阴离子（O(2)(·-)）的相关性。然后，42 例接受择期冠状动脉旁路移植术的他汀类药物初治患者随机分为阿托伐他汀 40mg/d 或安慰剂治疗 3 天，以观察阿托伐他汀对乳内动脉内皮功能和 O(2)(·-)生成的影响。最后，我们使用 26 例患者的乳内动脉段进行离体实验，以评估调节血管氧化还原状态的他汀类药物相关机制。他汀类药物治疗与乳内动脉一氧化氮生物利用度改善和 O(2)(·-)生成减少相关。口服阿托伐他汀可增加血管四氢生物蝶呤生物利用度，并独立于降低低密度脂蛋白而降低基础和 N-硝基-L-精氨酸甲酯抑制的 O(2)(·-)。在离体实验中，阿托伐他汀通过上调 GTP 环水解酶 I 基因表达和活性迅速改善血管四氢生物蝶呤生物利用度，从而改善内皮型一氧化氮合酶偶联并减少血管超氧阴离子（O(2)(·-)）。这些作用被甲羟戊酸逆转，表明血管羟甲基戊二酰基辅酶 A 还原酶抑制的直接作用。
本研究首次在人体中证明了他汀类药物治疗对血管壁的直接作用，支持这一作用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型一氧化氮合酶偶联直接改善血管一氧化氮生物利用度并减少血管超氧阴离子（O(2)(·-)）。这些发现为他汀类药物在人体中发挥有益的血管作用的机制提供了新的见解。
