{"title":"一氧化氮通过调节血红蛋白的氧转运改善小鼠缺氧的影响","authors":"Xiaoying Zhou, Wenting Su, Quanwei Bao, Yu Cui, Xiaoxu Li, Yidong Yang, Chengzhong Yang, Chengyuan Wang, Li Jiao, Dewei Chen, Jian Huang","doi":"10.1089/ham.2023.0044","DOIUrl":null,"url":null,"abstract":"<p><p>Xiaoying Zhou, Wenting Su, Quanwei Bao, Yu Cui, Xiaoxu Li, Yidong Yang, Chengzhong Yang, Chengyuan Wang, Li Jiao, Dewei Chen, and Jian Huang. Nitric oxide ameliorates the effects of hypoxia in mice by regulating oxygen transport by hemoglobin. <i>High Alt Med Biol</i>. 25:174-185, 2024.-Hypoxia is a common pathological and physiological phenomenon in ischemia, cancer, and strenuous exercise. Nitric oxide (NO) acts as an endothelium-derived relaxing factor in hypoxic vasodilation and serves as an allosteric regulator of hemoglobin (Hb). However, the ultimate effects of NO on the hematological system <i>in vivo</i> remain unknown, especially in extreme environmental hypoxia. Whether NO regulation of the structure of Hb improves oxygen transport remains unclear. Hence, we examined whether NO altered the oxygen affinity of Hb (Hb-O<sub>2</sub> affinity) to protect extremely hypoxic mice. Mice were exposed to severe hypoxia with various concentrations of NO, and the survival time, exercise capacity, and other physical indexes were recorded. The survival time was prolonged in the 5 ppm NO (6.09 ± 1.29 minutes) and 10 ppm NO (6.39 ± 1.58 minutes) groups compared with the 0 ppm group (4.98 ± 1.23 minutes). Hypoxia of the brain was relieved, and the exercise exhaustion time was prolonged when mice inhaled 20 ppm NO (24.70 ± 6.87 minutes vs. 20.23 ± 6.51 minutes). In addition, the differences in arterial oxygen saturation (SO<sub>2</sub>%) (49.64 ± 7.29% vs. 42.90 ± 4.30%) and arteriovenous SO<sub>2</sub>% difference (25.14 ± 8.95% vs. 18.10 ± 6.90%) obviously increased. In <i>ex vivo</i> experiments, the oxygen equilibrium curve (OEC) left shifted as P50 decreased from 43.77 ± 2.49 mmHg (0 ppm NO) to 40.97 ± 1.40 mmHg (100 ppm NO) and 38.36 ± 2.78 mmHg (200 ppm NO). Furthermore, the Bohr effect of Hb was enhanced by the introduction of 200 ppm NO (-0.72 ± 0.062 vs.-0.65 ± 0.051), possibly allowing Hb to more easily offload oxygen in tissue at lower pH. The crystal structure reveals a greater distance between Asp94β-His146β in nitrosyl -Hb(NO-Hb), NO-HbβCSO93, and S-NitrosoHb(SNO-Hb) compared to tense Hb(T-Hb, 3.7 Å, 4.3 Å, and 5.8 Å respectively, versus 3.5 Å for T-Hb). Moreover, hydrogen bonds were less likely to form, representing a key limitation of relaxed Hb (R-Hb). Upon NO interaction with Hb, hydrogen bonds and salt bridges were less favored, facilitating relaxation. We speculated that NO ameliorated the effects of hypoxia in mice by promoting erythrocyte oxygen loading in the lung and offloading in tissues.</p>","PeriodicalId":12975,"journal":{"name":"High altitude medicine & biology","volume":" ","pages":"174-185"},"PeriodicalIF":1.6000,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Nitric Oxide Ameliorates the Effects of Hypoxia in Mice by Regulating Oxygen Transport by Hemoglobin.\",\"authors\":\"Xiaoying Zhou, Wenting Su, Quanwei Bao, Yu Cui, Xiaoxu Li, Yidong Yang, Chengzhong Yang, Chengyuan Wang, Li Jiao, Dewei Chen, Jian Huang\",\"doi\":\"10.1089/ham.2023.0044\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Xiaoying Zhou, Wenting Su, Quanwei Bao, Yu Cui, Xiaoxu Li, Yidong Yang, Chengzhong Yang, Chengyuan Wang, Li Jiao, Dewei Chen, and Jian Huang. Nitric oxide ameliorates the effects of hypoxia in mice by regulating oxygen transport by hemoglobin. <i>High Alt Med Biol</i>. 25:174-185, 2024.-Hypoxia is a common pathological and physiological phenomenon in ischemia, cancer, and strenuous exercise. Nitric oxide (NO) acts as an endothelium-derived relaxing factor in hypoxic vasodilation and serves as an allosteric regulator of hemoglobin (Hb). However, the ultimate effects of NO on the hematological system <i>in vivo</i> remain unknown, especially in extreme environmental hypoxia. Whether NO regulation of the structure of Hb improves oxygen transport remains unclear. Hence, we examined whether NO altered the oxygen affinity of Hb (Hb-O<sub>2</sub> affinity) to protect extremely hypoxic mice. Mice were exposed to severe hypoxia with various concentrations of NO, and the survival time, exercise capacity, and other physical indexes were recorded. The survival time was prolonged in the 5 ppm NO (6.09 ± 1.29 minutes) and 10 ppm NO (6.39 ± 1.58 minutes) groups compared with the 0 ppm group (4.98 ± 1.23 minutes). Hypoxia of the brain was relieved, and the exercise exhaustion time was prolonged when mice inhaled 20 ppm NO (24.70 ± 6.87 minutes vs. 20.23 ± 6.51 minutes). In addition, the differences in arterial oxygen saturation (SO<sub>2</sub>%) (49.64 ± 7.29% vs. 42.90 ± 4.30%) and arteriovenous SO<sub>2</sub>% difference (25.14 ± 8.95% vs. 18.10 ± 6.90%) obviously increased. In <i>ex vivo</i> experiments, the oxygen equilibrium curve (OEC) left shifted as P50 decreased from 43.77 ± 2.49 mmHg (0 ppm NO) to 40.97 ± 1.40 mmHg (100 ppm NO) and 38.36 ± 2.78 mmHg (200 ppm NO). Furthermore, the Bohr effect of Hb was enhanced by the introduction of 200 ppm NO (-0.72 ± 0.062 vs.-0.65 ± 0.051), possibly allowing Hb to more easily offload oxygen in tissue at lower pH. The crystal structure reveals a greater distance between Asp94β-His146β in nitrosyl -Hb(NO-Hb), NO-HbβCSO93, and S-NitrosoHb(SNO-Hb) compared to tense Hb(T-Hb, 3.7 Å, 4.3 Å, and 5.8 Å respectively, versus 3.5 Å for T-Hb). Moreover, hydrogen bonds were less likely to form, representing a key limitation of relaxed Hb (R-Hb). Upon NO interaction with Hb, hydrogen bonds and salt bridges were less favored, facilitating relaxation. We speculated that NO ameliorated the effects of hypoxia in mice by promoting erythrocyte oxygen loading in the lung and offloading in tissues.</p>\",\"PeriodicalId\":12975,\"journal\":{\"name\":\"High altitude medicine & biology\",\"volume\":\" \",\"pages\":\"174-185\"},\"PeriodicalIF\":1.6000,\"publicationDate\":\"2024-09-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"High altitude medicine & biology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1089/ham.2023.0044\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/5/14 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q4\",\"JCRName\":\"BIOPHYSICS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"High altitude medicine & biology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1089/ham.2023.0044","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/5/14 0:00:00","PubModel":"Epub","JCR":"Q4","JCRName":"BIOPHYSICS","Score":null,"Total":0}
引用次数: 0
摘要
周晓颖、苏文婷、鲍全伟、崔宇、李晓旭、杨一东、杨承忠、王成元、焦莉、陈德伟和黄健。一氧化氮通过调节血红蛋白的氧运输改善小鼠缺氧的影响缺氧是缺血、癌症和剧烈运动中常见的病理和生理现象。一氧化氮(NO)在缺氧性血管扩张中充当内皮源性松弛因子,并充当血红蛋白(Hb)的异位调节因子。然而,NO 对体内血液系统的最终影响仍然未知,尤其是在极端缺氧的环境中。NO 对 Hb 结构的调节是否能改善氧的运输仍不清楚。因此,我们研究了 NO 是否会改变 Hb 的氧亲和力(Hb-O2 亲和力)以保护极度缺氧的小鼠。将小鼠暴露于不同浓度的 NO 的严重缺氧环境中,记录小鼠的存活时间、运动能力和其他身体指标。与 0 ppm 组(4.98 ± 1.23 分钟)相比,5 ppm NO 组(6.09 ± 1.29 分钟)和 10 ppm NO 组(6.39 ± 1.58 分钟)的存活时间延长。当小鼠吸入 20 ppm NO 时,脑缺氧得到缓解,运动耗竭时间延长(24.70 ± 6.87 分钟 vs. 20.23 ± 6.51 分钟)。此外,动脉血氧饱和度(SO2%)差异(49.64 ± 7.29% vs. 42.90 ± 4.30%)和动静脉 SO2% 差异(25.14 ± 8.95% vs. 18.10 ± 6.90%)明显增加。在体内外实验中,氧平衡曲线(OEC)左移,P50 从 43.77 ± 2.49 mmHg(0 ppm NO)下降到 40.97 ± 1.40 mmHg(100 ppm NO)和 38.36 ± 2.78 mmHg(200 ppm NO)。此外,引入 200 ppm NO 后,Hb 的玻尔效应增强(-0.72 ± 0.062 vs. -0.65 ± 0.051),这可能使 Hb 更容易在较低 pH 值下卸载组织中的氧气。晶体结构显示,在亚硝基-Hb(NO-Hb)、NO-HbβCSO93 和 S-亚硝基Hb(SNO-Hb)中,Asp94β-His146β 之间的距离比正常 Hb(T-Hb,分别为 3.7 Å、4.3 Å 和 5.8 Å,而 T-Hb 为 3.5 Å)要大。此外,氢键不太可能形成,这是弛缓 Hb(R-Hb)的一个关键局限。NO 与 Hb 相互作用时,氢键和盐桥的形成较少,从而促进了弛豫。我们推测,NO 通过促进红细胞在肺中的氧负荷和组织中的氧卸载,改善了小鼠缺氧的影响。
Nitric Oxide Ameliorates the Effects of Hypoxia in Mice by Regulating Oxygen Transport by Hemoglobin.
Xiaoying Zhou, Wenting Su, Quanwei Bao, Yu Cui, Xiaoxu Li, Yidong Yang, Chengzhong Yang, Chengyuan Wang, Li Jiao, Dewei Chen, and Jian Huang. Nitric oxide ameliorates the effects of hypoxia in mice by regulating oxygen transport by hemoglobin. High Alt Med Biol. 25:174-185, 2024.-Hypoxia is a common pathological and physiological phenomenon in ischemia, cancer, and strenuous exercise. Nitric oxide (NO) acts as an endothelium-derived relaxing factor in hypoxic vasodilation and serves as an allosteric regulator of hemoglobin (Hb). However, the ultimate effects of NO on the hematological system in vivo remain unknown, especially in extreme environmental hypoxia. Whether NO regulation of the structure of Hb improves oxygen transport remains unclear. Hence, we examined whether NO altered the oxygen affinity of Hb (Hb-O2 affinity) to protect extremely hypoxic mice. Mice were exposed to severe hypoxia with various concentrations of NO, and the survival time, exercise capacity, and other physical indexes were recorded. The survival time was prolonged in the 5 ppm NO (6.09 ± 1.29 minutes) and 10 ppm NO (6.39 ± 1.58 minutes) groups compared with the 0 ppm group (4.98 ± 1.23 minutes). Hypoxia of the brain was relieved, and the exercise exhaustion time was prolonged when mice inhaled 20 ppm NO (24.70 ± 6.87 minutes vs. 20.23 ± 6.51 minutes). In addition, the differences in arterial oxygen saturation (SO2%) (49.64 ± 7.29% vs. 42.90 ± 4.30%) and arteriovenous SO2% difference (25.14 ± 8.95% vs. 18.10 ± 6.90%) obviously increased. In ex vivo experiments, the oxygen equilibrium curve (OEC) left shifted as P50 decreased from 43.77 ± 2.49 mmHg (0 ppm NO) to 40.97 ± 1.40 mmHg (100 ppm NO) and 38.36 ± 2.78 mmHg (200 ppm NO). Furthermore, the Bohr effect of Hb was enhanced by the introduction of 200 ppm NO (-0.72 ± 0.062 vs.-0.65 ± 0.051), possibly allowing Hb to more easily offload oxygen in tissue at lower pH. The crystal structure reveals a greater distance between Asp94β-His146β in nitrosyl -Hb(NO-Hb), NO-HbβCSO93, and S-NitrosoHb(SNO-Hb) compared to tense Hb(T-Hb, 3.7 Å, 4.3 Å, and 5.8 Å respectively, versus 3.5 Å for T-Hb). Moreover, hydrogen bonds were less likely to form, representing a key limitation of relaxed Hb (R-Hb). Upon NO interaction with Hb, hydrogen bonds and salt bridges were less favored, facilitating relaxation. We speculated that NO ameliorated the effects of hypoxia in mice by promoting erythrocyte oxygen loading in the lung and offloading in tissues.
期刊介绍:
High Altitude Medicine & Biology is the only peer-reviewed journal covering the medical and biological issues that impact human life at high altitudes. The Journal delivers critical findings on the impact of high altitude on lung and heart disease, appetite and weight loss, pulmonary and cerebral edema, hypertension, dehydration, infertility, and other diseases. It covers the full spectrum of high altitude life sciences from pathology to human and animal ecology.