Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension
Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension
复制标题
DOI：
10.1172/jci200314172
复制
发表时间：
2003-04-01
影响因子：
15.9
通讯作者：
Harrison, DG
中科院分区：
文献类型：
--
作者：
Landmesser, U;Dikalov, S;Harrison, DG
四氢生物蝶呤是NO合成酶的关键辅因子，并且在其不存在的情况下，这些酶变得“解偶联”，产生活性氧（ROS）而不是NO。在具有脱氧皮质酮乙酸盐（DOCA盐）高血压的小鼠的动脉瘤中，NO合成酶的ROS产生显著增加，并且四氢生物蝶呤氧化是明显的。使用NADPH氧化酶亚基p47（phox）和小鼠缺乏内皮或神经元NO合酶缺陷的小鼠，我们获得的证据表明，高血压产生的级联反应涉及从NADPH氧化酶生产ROS，导致四氢生物蝶呤的氧化和解偶联内皮NO合酶（eNOS）。这减少了NO的产生并增加了eNOS的ROS产生。用口服四氢生物蝶呤治疗小鼠减少血管ROS产生，通过亚硝基血红蛋白的电子自旋共振测量确定增加NO产生，并减弱由于DOCA盐高血压引起的血压升高。内皮依赖性血管舒张在DOCA-盐高血压小鼠的血管中仅发生最小程度的改变，但似乎是由未偶联的eNOS释放的过氧化氢介导的，因为它被过氧化氢酶抑制。四氢生物蝶呤氧化可能是高血压的重要异常。增加四氢生物蝶呤或防止其氧化的治疗策略可能有助于预防这种常见疾病的血管并发症。
Tetrahydrobiopterin is a critical cofactor for the NO synthases, and in its absence these enzymes become "uncoupled," producing reactive oxygen species (ROSs) rather than NO. In aortas of mice with deoxycorticosterone acetate-salt (DOCA-salt) hypertension, ROS production from NO synthase is markedly increased, and tetrahydrobiopterin oxidation is evident. Using mice deficient in the NADPH oxidase subunit p47(phox) and mice lacking either the endothelial or neuronal NO synthase, we obtained evidence that hypertension produces a cascade involving production of ROSs from the NADPH oxidase leading to oxidation of tetrahydrobiopterin and uncoupling of endothelial NO synthase (eNOS). This decreases NO production and increases ROS production from eNOS. Treatment of mice with oral tetrahydrobiopterin reduces vascular ROS production, increases NO production as determined by electron spin resonance measurements of nitrosyl hemoglobin, and blunts the increase in blood pressure due to DOCA-salt hypertension. Endothelium-dependent vasodilation is only minimally altered in vessels of mice with DOCA-salt hypertension but seems to be mediated by hydrogen peroxide released from uncoupled eNOS, since it is inhibited by catalase. Tetrahydrobiopterin oxidation may represent an important abnormality in hypertension. Treatment strategies that increase tetrahydrobiopterin or prevent its oxidation may prove useful in preventing vascular complications of this common disease.