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

  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.