Increased hemoglobin affinity for oxygen with GBT1118 improves hypoxia tolerance in sickle cell mice
Increased hemoglobin affinity for oxygen with GBT1118 improves hypoxia tolerance in sickle cell mice
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DOI：
10.1152/ajpheart.00048.2021
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发表时间：
2021-08-01
影响因子：
4.8
通讯作者：
Cabrales, Pedro
中科院分区：
文献类型：
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作者：
Dufu, Kobina;Williams, Alexander T.;Cabrales, Pedro
理论上，增加 Hb 对氧 (O-2) 亲和力的治疗药物可能会导致 Hb 释放的 O-2 减少，并对组织造成缺氧风险。在本研究中，GBT1118（一种 Hb 对 O-2 亲和力的变构调节剂）用于评估增加 Hb 对 O-2 亲和力对 Townes 转基因镰状细胞病 (SCD) 小鼠脑组织氧合、血压、心率、O-2 输送和缺氧耐受性的影响。研究了常氧和严重缺氧挑战期间的脑氧合和 O-2 输送。 GBT1118 的长期治疗增加了 Hb 对 O-2 的亲和力，将 SCD 小鼠中 50% HbO(2) 饱和度 (P50) 的 PO2 从 31mmHg 降低至 18mmHg。这种治疗显着减少了贫血，使血细胞比容增加了 33%，改善了心输出量 (CO) 以及 O-2 输送和提取。使用 GBT1118 长期增加 Hb 对 O-2 的亲和力可在常氧期间保持皮质 O-2 张力，改善缺氧期间的皮质 O-2 张力，并提高 SCD 小鼠对严重缺氧的耐受性。与慢性治疗引起的血液学变化无关，单剂量 GBT1118 显着提高了对缺氧的耐受性，突出了增加 Hb 对 O-2 亲和力的好处，从而减少了 SCD 缺氧期间血液中红细胞的镰状化。网织红细胞计数减少。此外，长期增加的血红蛋白对氧的亲和力显着改善了缺氧期间镰状细胞病小鼠的存活率以及皮质组织氧合，这表明通过增加血红蛋白对氧的亲和力可以改善氧气的输送和利用。
Therapeutic agents that increase the Hb affinity for oxygen (O-2) could, in theory, lead to decreased O-2 release from Hb and impose a hypoxic risk to tissues. In this study, GBT1118, an allosteric modifier of Hb affinity for O-2, was used to assess the impact of increasing Hb affinity for O-2 on brain tissue oxygenation, blood pressure, heart rate, O-2 delivery, and tolerance to hypoxia in Townes transgenic sickle cell disease (SCD) mice. Brain oxygenation and O-2 delivery were studied during normoxia and severe hypoxic challenges. Chronic treatment with GBT1118 increased Hb affinity for O-2, reducing the PO2 for 50% HbO(2) saturation (P50) in SCD mice from 31mmHg to 18mmHg. This treatment significantly reduced anemia, increasing hematocrit by 33%, improved cardiac output (CO), and O-2 delivery and extraction. Chronically increasing Hb affinity for O-2 with GBT1118 preserved cortical O-2 tension during normoxia, improved cortical O-2 tension during hypoxia, and increased tolerance to severe hypoxia in SCD mice. Independent of hematological changes induced by chronic treatment, a single dose of GBT1118 significantly improved tolerance to hypoxia, highlighting the benefits of increasing Hb affinity for O-2 and consequently reducing sickling of RBCs in blood during hypoxia in SCD.NEW & NOTEWORTHY Chronic pharmacologically increased hemoglobin affinity for oxygen in sickle cell disease mice alleviated hematological consequences of sickle cell disease, increasing RBC half-life, hematocrit, and hemoglobin concentration, while also decreasing reticulocyte count. Additionally, chronically increased hemoglobin affinity for oxygen significantly improved survival as well as cortical tissue oxygenation in sickle cell disease mice during hypoxia, suggesting that oxygen delivery and utilization is improved by increased hemoglobin affinity for oxygen.