Altered plasma versus vascular biopterins in human atherosclerosis reveal relationships between endothelial nitric oxide synthase coupling, endothelial function, and inflammation
Altered plasma versus vascular biopterins in human atherosclerosis reveal relationships between endothelial nitric oxide synthase coupling, endothelial function, and inflammation
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DOI：
10.1161/circulationaha.107.704155
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发表时间：
2007-12-11
期刊：
影响因子：
37.8
通讯作者：
Channon, Keith M.
中科院分区：
文献类型：
--
作者：
Antoniades, Charalambos;Shirodaria, Cheerag;Channon, Keith M.
背景-四氢生物蝶呤（BH 4）是内皮型一氧化氮合酶（eNOS）活性和偶联的关键调节剂。然而，血管和/或全身BH 4水平在人类动脉粥样硬化中改变的程度以及BH 4生物利用度在确定内皮功能和氧化应激中的重要性仍不清楚。我们试图定义血浆和血管生物喋呤水平之间的关系，在冠心病患者，并确定如何BH 4水平影响内皮功能，eNOS耦合，血管超氧化物production.Methods和结果隐静脉和内乳动脉的样本收集了219例冠状动脉疾病患者接受冠状动脉旁路移植术。我们测定了血浆和血管中生物蝶呤的水平，血管对乙酰胆碱的反应，以及在存在和不存在eNOS抑制剂N-G-硝基-L-精氨酸甲酯的情况下血管超氧化物的产生。血管BH_4浓度高时，血管对乙酰胆碱的舒张作用强（P < 0.05），而血浆BH_4浓度高时，血管对乙酰胆碱的舒张作用弱（P < 0.05）。此外，在血浆和血管生物喋呤之间观察到负相关（隐静脉和乳内动脉均P < 0.05）。高血管（而非血浆）BH 4与总超氧化物和NG-硝基-L-精氨酸甲酯可抑制的超氧化物的减少相关，表明eNOS偶联的改善。最后，血浆而非血管生物蝶呤水平与血浆C反应蛋白水平相关（P < 0.001）。结论：冠心病患者血浆和血管生物蝶呤之间存在负相关。血管而不是血浆BH 4是人体血管中eNOS偶联、内皮依赖性血管舒张和超氧化物产生的重要决定因素，而血浆生物蝶呤是全身性炎症的标志物。
Background-Tetrahydrobiopterin ( BH4) is a key regulator of endothelial nitric oxide synthase (eNOS) activity and coupling. However, the extent to which vascular and/or systemic BH4 levels are altered in human atherosclerosis and the importance of BH4 bioavailability in determining endothelial function and oxidative stress remain unclear. We sought to define the relationships between plasma and vascular biopterin levels in patients with coronary artery disease and to determine how BH4 levels affect endothelial function, eNOS coupling, and vascular superoxide production.Methods and Results-Samples of saphenous veins and internal mammary arteries were collected from 219 patients with coronary artery disease undergoing coronary artery bypass grafting. We determined plasma and vascular levels of biopterins, vasomotor responses to acetylcholine, and vascular superoxide production in the presence and absence of the eNOS inhibitor N-G-nitro-L-arginine methyl ester. High vascular BH4 was associated with greater vasorelaxations to acetylcholine (P < 0.05), whereas high plasma BH4 was associated with lower vasorelaxations in response to acetylcholine (P < 0.05). Furthermore, an inverse association was observed between plasma and vascular biopterins (P < 0.05 for both saphenous veins and internal mammary arteries). High vascular (but not plasma) BH4 was associated with reduced total and NG-nitro-L-arginine methyl ester-inhibitable superoxide, suggesting improved eNOS coupling. Finally, plasma but not vascular biopterin levels were correlated with plasma C-reactive protein levels (P < 0.001).Conclusions-An inverse association exists between plasma and vascular biopterins in patients with coronary artery disease. Vascular but not plasma BH4 is an important determinant of eNOS coupling, endothelium-dependent vasodilation, and superoxide production in human vessels, whereas plasma biopterins are a marker of systemic inflammation.