Department of Physiology and Center for Pulmonary Hypertension, New York Medical College, Valhalla, NY 10595, USA.
Cardiol Rev. 2010 Mar-Apr;18(2):89-93. doi: 10.1097/CRD.0b013e3181c9f088.
Most current theories for the mechanism of hypoxic pulmonary vasoconstriction (HPV) include a role for reactive oxygen species and/or changes in redox regulation, but extreme controversy exists regarding which systems and redox changes mediate the HPV response. Nitric oxide (NO) appears to help to maintain low pulmonary arterial pressure, suppress HPV, and prevent the development of pulmonary hypertension. Our studies have found a key role for glucose-6-phosphate dehydrogenase in bovine pulmonary arterial smooth muscle functioning to maintain elevated levels of cytosolic NADPH which fuels the generation of vasodilator levels of hydrogen peroxide. HPV results from hypoxia removing vasodilation by peroxide. Decreased superoxide generation by Nox4 oxidase and its conversion to peroxide by Cu,Zn-SOD appear to be potential factors in sensing hypoxia, and decreased cGMP-associated vasodilation and removal of redox controlled vasodilator mechanisms by increased cytosolic NADPH may be key coordinators of the HPV response. Oxidant generation associated with vascular disease processes, including the removal of NO by superoxide, and attenuation of its ability to stimulate cGMP production by oxidation of the heme and thiols of soluble guanylate cyclase attenuate potential beneficial actions of NO on pulmonary arterial function. While pulmonary hypertension appears to have multiple poorly understood effects on redox-associated processes, potentially influencing responses to hypoxia and NO-cGMP signaling, much remains to be elucidated regarding how these processes may be important factors in the progression, expression and therapeutic treatment of pulmonary hypertension.
目前大多数关于低氧性肺血管收缩（HPV）机制的理论都包括活性氧（ROS）和/或氧化还原调节变化的作用，但对于哪些系统和氧化还原变化介导 HPV 反应存在极大的争议。一氧化氮（NO）似乎有助于维持低肺动脉压、抑制 HPV 并预防肺动脉高压的发展。我们的研究发现，葡萄糖-6-磷酸脱氢酶（G6PD）在牛肺动脉平滑肌中的功能中起着关键作用，可维持细胞溶质 NADPH 的高水平，从而为生成血管扩张剂水平的过氧化氢提供燃料。HPV 是由缺氧通过过氧化物去除血管扩张作用引起的。Nox4 氧化酶生成的超氧化物减少及其被 Cu，Zn-SOD 转化为过氧化物，似乎是感应缺氧的潜在因素，而细胞溶质 NADPH 增加导致 cGMP 相关血管舒张和去除氧化还原控制的血管舒张机制，可能是 HPV 反应的关键协调因素。与血管疾病过程相关的氧化生成，包括通过超氧化物去除 NO 及其通过氧化可溶性鸟苷酸环化酶的血红素和硫醇来削弱其刺激 cGMP 产生的能力，会削弱 NO 对肺动脉功能的潜在有益作用。虽然肺动脉高压似乎对与氧化还原相关的过程有多种尚未完全了解的影响，可能会影响对缺氧和 NO-cGMP 信号的反应，但关于这些过程如何成为肺动脉高压进展、表达和治疗的重要因素，仍有许多问题需要阐明。
