Antoniades Charalambos, Shirodaria Cheerag, Crabtree Mark, Rinze Ruth, Alp Nicholas, Cunnington Colin, Diesch Jonathan, Tousoulis Dimitris, Stefanadis Christodoulos, Leeson Paul, Ratnatunga Chandi, Pillai Ravi, Channon Keith M
Department of Cardiovascular Medicine, University of Oxford, Oxford, UK.
Circulation. 2007 Dec 11;116(24):2851-9. doi: 10.1161/CIRCULATIONAHA.107.704155. Epub 2007 Nov 26.
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.
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 N(G)-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).
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.
四氢生物蝶呤（BH4）是内皮型一氧化氮合酶（eNOS）活性和偶联的关键调节因子。然而，人类动脉粥样硬化中血管和/或全身BH4水平改变的程度以及BH4生物利用度在决定内皮功能和氧化应激方面的重要性仍不清楚。我们试图确定冠心病患者血浆和血管生物蝶呤水平之间的关系，并确定BH4水平如何影响内皮功能、eNOS偶联和血管超氧化物生成。
从219例接受冠状动脉旁路移植术的冠心病患者中采集大隐静脉和乳内动脉样本。我们测定了生物蝶呤的血浆和血管水平、对乙酰胆碱的血管舒缩反应以及在有和没有eNOS抑制剂N（G）-硝基-L-精氨酸甲酯存在时的血管超氧化物生成情况。高血管BH4与对乙酰胆碱的更大血管舒张相关（P<0.05），而高血浆BH4与对乙酰胆碱的较低血管舒张相关（P<0.05）。此外，在血浆和血管生物蝶呤之间观察到负相关（大隐静脉和乳内动脉均为P<0.05）。高血管（而非血浆）BH4与总超氧化物和N（G）-硝基-L-精氨酸甲酯可抑制的超氧化物减少相关，提示eNOS偶联改善。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）。
冠心病患者血浆和血管生物蝶呤之间存在负相关。血管而非血浆BH4是人类血管中eNOS偶联、内皮依赖性血管舒张和超氧化物生成的重要决定因素，而血浆生物蝶呤是全身炎症的标志物。
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