Macitentan Attenuates Chronic Mountain Sickness in Rats by Regulating Arginine and Purine Metabolism

Abstract

Chronic mountain sickness (CMS) is a high altitude complication with high rates of morbidity and mortality. CMS is characterized by high-altitude polycythemia (HAPC) and high-altitude pulmonary hypertension (HAPH). In this study, macitentan, a dual endothelin receptor antagonist, was used to treat CMS, and the induced metabolomics changes were studied. CMS was induced in rats in a hypobaric hypoxia chamber (simulating a 5500 m plateau) for 4 weeks. Macitentan was administered in the third and fourth weeks (30 mg·kg–1·day–1). At the end of the follow-up period, we performed echocardiography, measured hemodynamic parameters and hematocrit, and performed histological staining. Furthermore, ultraperformance liquid chromatography-mass spectrometry (UPLC–MS)-based metabolic analysis was applied to explore metabolic changes associated with hypobaric hypoxia, with or without macitentan. qRT-PCR and kits for the determination of xanthine oxidase (XO) activity were used for validation experiments. Macitentan was effective in attenuating CMS, including CMS-induced right ventricle hypertrophy, HAPC, and HAPH. The levels of 48 metabolites were significantly changed in the CMS model group compared to the control group. Of these changes, 21 were reversed by treatment with macitentan. Enrichment analysis revealed that the purine metabolism pathway, as well as the arginine/proline metabolism pathway, might be the key pathways adjusted by macitentan. Furthermore, we verified macitentan played a beneficial role by directly regulating the expression of arginine1 and arginine2 in the arginine/proline metabolic pathway, and the activity of xanthine oxidase in the purine metabolic pathway. In conclusion, this study demonstrated that macitentan significantly ameliorated CMS in rats, and the mechanism was attributed to the reversion of the disorder in purine and arginine/proline metabolism, via direct regulation of XO activity and arginine1/2 expression. These findings are expected to provide new insights into the therapeutics and mechanism of macitentan in CMS.

Oxidative Stress and Diseases Associated with High-Altitude Exposure

“…Moreover, a study on rats with CMS induced by chronic hypobaric hypoxia (5000 m; 30 days) demonstrated that in the CMS model group, the MDA level was significantly higher than that in the control group, and the concentrations of SOD and GPx were decreased [ 67 ]. Additionally, through a proteomic and metabolomics analysis, a recent study on rats with CMS induced by 28-day exposure to hypobaric hypoxia reported an increase in 8-hydroxyguanosine and trimethylamine N-oxide, which were associated with oxidative stress and pulmonary vasoconstriction processes, respectively [ 68 ] ( Table 1 ).…”

Tibetan Medicine Duoxuekang Capsule Ameliorates High-Altitude Polycythemia Accompanied by Brain Injury

“…Some evidences show that the prevalence of CMS in high-altitude populations varies from 1.2 to 33% ( Bao et al, 2017 ) and is about 20% among Andean highlanders ( Yao et al, 2018 ). Synchronously, CMS is characterized by high-altitude polycythemia (HAPC) and high-altitude pulmonary hypertension ( Gao et al, 2020 ). Furthermore, patients with HAPC experience venectasia, attention-deficit disorder, and lapse of memory ( Liu et al, 2018 ).…”

Analysis of Metabolic Markers in Patients with Chronic Heart Failure before and after LVAD Implantation

“…Only one amino acid returned to control concentrations >100 days post-LVAD HF. Proline is an important player in glutamate metabolism and, as such, is involved in different signaling pathways, including metabolic reprogramming [43,44], senescence [45], and apoptosis [46,47]. Wang et al recently showed that Pro acts a cardioprotective agent by reducing reactive oxygen species in vitro [48].…”