罗沙司他对急性高原低氧心脏功能适应的作用及其机制

郭莉; 肖春红; 卢振兴; 张茹; 杨爱林; 季乐乐; 郭春霞; 海碣石; 郭海涛

doi:10.12125/j.chj.202106086

罗沙司他对急性高原低氧心脏功能适应的作用及其机制

Effect and mechanism of Roxadustat on cardiac function adaptation of acute hypoxia at high altitude

摘要

摘要:
目的探讨PHD2抑制剂罗沙司他对模拟海拔5 000 m高原低氧环境小鼠心脏功能适应的作用及其机制。
方法 40只雄性C57BL/6J小鼠随机分为4组：常氧组、罗沙司他（100 mg/kg）+常氧组、低氧组、罗沙司他（100 mg/kg）+低氧组。低氧组小鼠置于ProOx-810L动物低压氧舱内饲养7 d；常氧组于常压常氧环境饲养。应用超声心动图、血常规、血生化综合评价高原低氧环境下小鼠心脏功能变化，Western Blotting分析HIF-1α和HIF-2α的表达水平。
结果高原低氧暴露下，小鼠体质量增长显著减缓，罗沙司他对高原低氧暴露下的小鼠没有明显的毒副作用。高原低氧7 d后小鼠左室舒张末期内径（LVIDd）显著减小（P<0.05），罗沙司他可增加LVIDd（P<0.05），提高心脏适应能力。高原低氧导致红细胞生成素（EPO）明显升高，红细胞计数（RBC）、血红蛋白（Hb）和红细胞压积（Hct）增加（P<0.01），该效应可被罗沙司他进一步增强RBC（P<0.01）、Hb（P<0.01）和Hct（P<0.05）。与常氧组比较，高原低氧可以显著增加小鼠心肌HIF-1α（P<0.05）、HIF-2α（P<0.01）和PHD2的蛋白表达水平（P<0.01），此效应可被罗沙司他进一步增强HIF-1α（P<0.01）、HIF-2α（P<0.01）和PHD2（P<0.05）。低氧条件下心肌损伤相关的血清乳酸脱氢酶（LDH）水平显著增高（P<0.01），罗沙司他可降低LDH水平，减轻低氧对心肌的损伤（P<0.01）。
结论罗沙司他可通过抑制PHD2活性上调HIF-1α和HIF-2α的蛋白水平，同时减轻心肌损伤，进而促进高原低氧环境下小鼠心脏功能的适应。

Abstract:
AIM To investigate the effects and mechanisms of Roxadustat on heart function adaptation in mice under simulated hypoxic environment at 5000 m altitude.
METHODS Forty male C57BL/6J mice were randomly divided into 4 groups: Normoxia group, Roxadustat (100 mg/kg) + Normoxia group, Hypoxia group, and Roxadustat (100 mg/kg) + Hypoxia group. Mice in hypoxia group were fed in ProOx-810L animal low-pressure oxygen chamber for 7 days. The Normoxia group was fed in the Normoxia environment at atmospheric pressure. The changes of heart function in mice under high altitude hypoxia were evaluated by echocardiography, blood routine and blood biochemical analysis. The expression levels of HIF-1α and HIF-2α were analyzed by Western Blotting.
RESULTS The body weight growth of mice was significantly slowed down under simulated hypoxia exposure, and the application of Roxadustat, a PHD2 inhibitor, had no obvious toxic and side effects on mice exposed to hypoxia at high altitude. After 7 days of high altitude hypoxia, the LVIDd of mice was significantly decreased (P<0.05), but Roxadustat improved the LVIDd (P<0.05) and the cardiac adaptability. High altitude hypoxia significantly increased EPO, RBC, Hb and Hct (P<0.01), and this effect was significantly enhanced by Roxadustat (RBC (P<0.01)、Hb (P<0.01) and Hct (P<0.05)). Compared with normal oxygen group, high altitude hypoxia significantly increased the protein expression levels of HIF-1α (P<0.05), HIF-2α (P<0.01) and PHD2 in myocardium of mice (P<0.05), and this effect was significantly enhanced by PHD2 Roxadustat (HIF-1α (P<0.01)、HIF-2α (P<0.01) and PHD2 (P<0.05)). The level of serum LDH, one indicator of myocardial injury, was significantly increased under hypoxia condition (P<0.01), and Roxadustat decreased LDH level and alleviated the myocardial injury caused by hypoxia (P<0.01).
CONCLUSION Roxadustat, which up-regulates the protein levels of HIF-1α and HIF-2α by inhibiting PHD2 activity and reduces the expression of injury-related enzymes, promotes the adaptation of heart function in mice under high altitude hypoxia environment.

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