Zhang Rongli, Hess Douglas T, Qian Zhaoxia, Hausladen Alfred, Fonseca Fabio, Chaube Ruchi, Reynolds James D, Stamler Jonathan S
Institute for Transformative Molecular Medicine and Departments of Medicine and.
Institute for Transformative Molecular Medicine and Anesthesiology, Case Western Reserve University School of Medicine, Cleveland, OH 44106; and.
Proc Natl Acad Sci U S A. 2015 May 19;112(20):6425-30. doi: 10.1073/pnas.1502285112. Epub 2015 Mar 25.
Oxygen delivery by Hb is essential for vertebrate life. Three amino acids in Hb are strictly conserved in all mammals and birds, but only two of those, a His and a Phe that stabilize the heme moiety, are needed to carry O2. The third conserved residue is a Cys within the β-chain (βCys93) that has been assigned a role in S-nitrosothiol (SNO)-based hypoxic vasodilation by RBCs. Under this model, the delivery of SNO-based NO bioactivity by Hb redefines the respiratory cycle as a triune system (NO/O2/CO2). However, the physiological ramifications of RBC-mediated vasodilation are unknown, and the apparently essential nature of βCys93 remains unclear. Here we report that mice with a βCys93Ala mutation are deficient in hypoxic vasodilation that governs blood flow autoregulation, the classic physiological mechanism that controls tissue oxygenation but whose molecular basis has been a longstanding mystery. Peripheral blood flow and tissue oxygenation are decreased at baseline in mutant animals and decline excessively during hypoxia. In addition, βCys93Ala mutation results in myocardial ischemia under basal normoxic conditions and in acute cardiac decompensation and enhanced mortality during transient hypoxia. Fetal viability is diminished also. Thus, βCys93-derived SNO bioactivity is essential for tissue oxygenation by RBCs within the respiratory cycle that is required for both normal cardiovascular function and circulatory adaptation to hypoxia.
血红蛋白（Hb）输送氧气对脊椎动物的生命至关重要。在所有哺乳动物和鸟类中，Hb的三个氨基酸严格保守，但其中只有两个，即稳定血红素部分的组氨酸（His）和苯丙氨酸（Phe），是携带氧气所必需的。第三个保守残基是β链内的半胱氨酸（βCys93），它在红细胞基于S-亚硝基硫醇（SNO）的低氧性血管舒张中发挥作用。在这个模型中，Hb输送基于SNO的一氧化氮（NO）生物活性将呼吸周期重新定义为一个三位一体系统（NO/氧气/二氧化碳）。然而，红细胞介导的血管舒张的生理后果尚不清楚，βCys93明显的本质重要性仍不明确。在此我们报告，具有βCys93Ala突变的小鼠在控制血流自动调节的低氧性血管舒张方面存在缺陷，血流自动调节是控制组织氧合的经典生理机制，但其分子基础长期以来一直是个谜。突变动物在基线时外周血流和组织氧合减少，在低氧期间过度下降。此外，βCys93Ala突变在基础常氧条件下导致心肌缺血，在短暂低氧期间导致急性心脏失代偿和死亡率增加。胎儿存活率也降低。因此，βCys93衍生的SNO生物活性对于呼吸周期中红细胞进行组织氧合至关重要，而这对于正常心血管功能和对低氧的循环适应都是必需的。
