Hypoxia, red blood cells, and nitrite regulate NO-dependent hypoxic vasodilation
Hypoxia, red blood cells, and nitrite regulate NO-dependent hypoxic vasodilation
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DOI：
10.1182/blood-2005-07-2668
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发表时间：
2006-01-15
期刊：
影响因子：
20.3
通讯作者：
Patel, RP
中科院分区：
文献类型：
--
作者：
Crawford, JH;Isbell, TS;Patel, RP
响应于缺氧的局部血管舒张是在代谢应激下确保氧递送到组织的基本生理反应。最近的研究确定了红细胞（RBC）的作用，血红蛋白是缺氧传感器。在此，我们研究了调节这一过程的机制，并探讨了三磷酸腺苷，S-亚硝基血红蛋白和亚硝酸盐作为效应子的相对作用。我们提供的证据表明，缺氧红细胞介导的血管舒张，减少亚硝酸盐一氧化氮（NO）和ATP的释放。NO依赖亚硝酸盐介导的血管舒张证明NO气体的形成，刺激cGMP的生产，并抑制线粒体呼吸的过程中敏感的NO清除剂C-PTIO。血红蛋白的亚硝酸盐还原酶活性受血红素脱氧和血红素氧化还原电位的调节，在50%血红蛋白氧合（P-50）时观察到最大活性。同时，在P-50处开始血管舒张，表明血红蛋白的氧感测与亚硝酸盐减少和血管舒张的刺激机制相关。保守的β 93半胱氨酸残基突变降低血红素氧化还原电位（即降低E-1/2），这一效应在任何给定的血红蛋白饱和度下都会增加亚硝酸盐还原酶活性和血管舒张。这些数据支持RBC血红蛋白作为变构和氧化还原调节的亚硝酸盐还原酶的功能，其“酶活性”将缺氧与增加的NO依赖性血流量偶联。
Local vasodilation in response to hypoxia is a fundamental physiologic response ensuring oxygen delivery to tissues under metabolic stress. Recent studies identify a role for the red blood cell (RBC), with hemoglobin the hypoxic sensor. Herein, we investigate the mechanisms regulating this process and explore the relative roles of adenosine triphosphate, S-nitrosohemoglobin, and nitrite as effectors. We provide evidence that hypoxic RBCs mediate vasodilation by reducing nitrite to nitric oxide (NO) and ATP release. NO dependence for nitrite-mediated vasodilation was evidenced by NO gas formation, stimulation of cGMP production, and inhibition of mitochondrial respiration in a process sensitive to the NO scavenger C-PTIO. The nitrite reductase activity of hemoglobin is modulated by heme deoxygenation and heme redox potential, with maximal activity observed at 50% hemoglobin oxygenation (P-50). Concomitantly, vasodilation is initiated at the P-50, suggesting that oxygen sensing by hemoglobin is mechanistically linked to nitrite reduction and stimulation of vasodilation. Mutation of the conserved beta 93cys residue decreases the heme redox potential (ie, decreases E-1/2), an effect that increases nitrite reductase activity and vasodilation at any given hemoglobin saturation. These data support a function for RBC hemoglobin as an allosterically and redox-regulated nitrite reductase whose "enzyme activity" couples hypoxia to increased NO-dependent blood flow.