From the Institute for Transformative Molecular Medicine (R.T.P., J.D.R., R.Z., J.S.S.), Case Western Reserve University School of Medicine, OH.
Harrington Discovery Institute (R.T.P., J.D.R., J.S.S.), University Hospitals Cleveland Medical Center, OH.
Circ Res. 2020 Jan 3;126(1):129-158. doi: 10.1161/CIRCRESAHA.119.315626. Epub 2019 Oct 8.
A continuous supply of oxygen is essential for the survival of multicellular organisms. The understanding of how this supply is regulated in the microvasculature has evolved from viewing erythrocytes (red blood cells [RBCs]) as passive carriers of oxygen to recognizing the complex interplay between Hb (hemoglobin) and oxygen, carbon dioxide, and nitric oxide-the three-gas respiratory cycle-that insures adequate oxygen and nutrient delivery to meet local metabolic demand. In this context, it is blood flow and not blood oxygen content that is the main driver of tissue oxygenation by RBCs. Herein, we review the lines of experimentation that led to this understanding of RBC function; from the foundational understanding of allosteric regulation of oxygen binding in Hb in the stereochemical model of Perutz, to blood flow autoregulation (hypoxic vasodilation governing oxygen delivery) observed by Guyton, to current understanding that centers on S-nitrosylation of Hb (ie, S-nitrosohemoglobin; SNO-Hb) as a purveyor of oxygen-dependent vasodilatory activity. Notably, hypoxic vasodilation is recapitulated by native S-nitrosothiol (SNO)-replete RBCs and by SNO-Hb itself, whereby SNO is released from Hb and RBCs during deoxygenation, in proportion to the degree of Hb deoxygenation, to regulate vessels directly. In addition, we discuss how dysregulation of this system through genetic mutation in Hb or through disease is a common factor in oxygenation pathologies resulting from microcirculatory impairment, including sickle cell disease, ischemic heart disease, and heart failure. We then conclude by identifying potential therapeutic interventions to correct deficits in RBC-mediated vasodilation to improve oxygen delivery-steps toward effective microvasculature-targeted therapies. To the extent that diseases of the heart, lungs, and blood are associated with impaired tissue oxygenation, the development of new therapies based on the three-gas respiratory system have the potential to improve the well-being of millions of patients.
多细胞生物的生存离不开持续的氧气供应。对微血管中氧气供应如何调节的认识，已经从将红细胞（红血球）视为氧气的被动载体，发展到认识到血红蛋白（Hb）与氧气、二氧化碳和一氧化氮之间的复杂相互作用——三气呼吸循环——这确保了足够的氧气和营养物质输送，以满足局部代谢需求。在这种情况下，是血流而不是血液中的氧含量，是红细胞为组织供氧的主要驱动因素。在此，我们回顾了导致对 RBC 功能这种理解的实验思路；从 Perutz 立体化学模型中对氧结合的变构调节的基本认识，到 Guyton 观察到的血流自动调节（缺氧性血管舒张控制氧气输送），再到目前的理解，即集中在 Hb 的 S-亚硝基化（即 S-亚硝基血红蛋白；SNO-Hb）作为氧气依赖性血管舒张活性的提供者。值得注意的是，缺氧性血管舒张可以通过天然的 S-亚硝酰巯基（SNO）充足的 RBC 和 SNO-Hb 本身来重现，在此过程中，SNO 在脱氧时从 Hb 和 RBC 中释放出来，与 Hb 脱氧的程度成比例，从而直接调节血管。此外，我们还讨论了通过 Hb 基因突变或疾病导致该系统失调，如何成为由于微循环受损导致的氧合病理的常见因素，包括镰状细胞病、缺血性心脏病和心力衰竭。然后，我们通过确定纠正 RBC 介导的血管舒张缺陷以改善氧气输送的潜在治疗干预措施来结束讨论——这是迈向有效微血管靶向治疗的一步。在一定程度上，与心脏、肺部和血液相关的疾病与组织缺氧有关，基于三气呼吸系统的新疗法有可能改善数百万患者的健康状况。
