PMID- 32640793
OWN - NLM
STAT- MEDLINE
DCOM- 20210617
LR  - 20210617
IS  - 1535-3907 (Electronic)
IS  - 1535-3893 (Linking)
VI  - 19
IP  - 8
DP  - 2020 Aug 7
TI  - Macitentan Attenuates Chronic Mountain Sickness in Rats by Regulating Arginine 
      and Purine Metabolism.
PG  - 3302-3314
LID - 10.1021/acs.jproteome.0c00219 [doi]
AB  - 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.
FAU - Gao, Xiaojian
AU  - Gao X
AUID- ORCID: 0000-0002-0510-9000
AD  - Department of Cardiovascular, Chinese PLA General Hospital, Beijing 100853, 
      China.
FAU - Zhang, Zeyu
AU  - Zhang Z
AD  - Department of Cardiovascular, Chinese PLA General Hospital, Beijing 100853, 
      China.
FAU - Li, Xin
AU  - Li X
AD  - Core Laboratory of Translational Medicine, Medical Innovation Research Division 
      of Chinese PLA General Hospital, Beijing 100853, China.
AD  - Beijing Key Laboratory of Chronic Heart Failure Precision Medicine, Chinese PLA 
      General Hospital, Beijing 100853, China.
FAU - Li, Chen
AU  - Li C
AD  - Core Laboratory of Translational Medicine, Medical Innovation Research Division 
      of Chinese PLA General Hospital, Beijing 100853, China.
AD  - Beijing Key Laboratory of Chronic Heart Failure Precision Medicine, Chinese PLA 
      General Hospital, Beijing 100853, China.
FAU - Hao, Jianxiu
AU  - Hao J
AD  - Core Laboratory of Translational Medicine, Medical Innovation Research Division 
      of Chinese PLA General Hospital, Beijing 100853, China.
AD  - Beijing Key Laboratory of Chronic Heart Failure Precision Medicine, Chinese PLA 
      General Hospital, Beijing 100853, China.
FAU - Luo, Yunfu
AU  - Luo Y
AD  - WuXi AppTec Co., Ltd., 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 
      200131, China.
FAU - Lei, Maoyi
AU  - Lei M
AD  - WuXi AppTec Co., Ltd., 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 
      200131, China.
FAU - Li, Junmiao
AU  - Li J
AD  - WuXi AppTec Co., Ltd., 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 
      200131, China.
FAU - Liu, Chunlei
AU  - Liu C
AD  - Core Laboratory of Translational Medicine, Medical Innovation Research Division 
      of Chinese PLA General Hospital, Beijing 100853, China.
AD  - Beijing Key Laboratory of Chronic Heart Failure Precision Medicine, Chinese PLA 
      General Hospital, Beijing 100853, China.
FAU - He, Kunlun
AU  - He K
AD  - Core Laboratory of Translational Medicine, Medical Innovation Research Division 
      of Chinese PLA General Hospital, Beijing 100853, China.
AD  - Beijing Key Laboratory of Chronic Heart Failure Precision Medicine, Chinese PLA 
      General Hospital, Beijing 100853, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200724
PL  - United States
TA  - J Proteome Res
JT  - Journal of proteome research
JID - 101128775
RN  - 0 (Purines)
RN  - 0 (Pyrimidines)
RN  - 0 (Sulfonamides)
RN  - 94ZLA3W45F (Arginine)
RN  - Z9K9Y9WMVL (macitentan)
SB  - IM
MH  - Altitude
MH  - *Altitude Sickness/drug therapy
MH  - Animals
MH  - Arginine
MH  - Chromatography, Liquid
MH  - Metabolic Networks and Pathways
MH  - Purines
MH  - Pyrimidines
MH  - Rats
MH  - Sulfonamides
MH  - Tandem Mass Spectrometry
OTO - NOTNLM
OT  - arginine
OT  - chronic mountain sickness
OT  - macitentan
OT  - metabolomics
OT  - purine
EDAT- 2020/07/10 06:00
MHDA- 2021/06/22 06:00
CRDT- 2020/07/10 06:00
PHST- 2020/07/10 06:00 [pubmed]
PHST- 2021/06/22 06:00 [medline]
PHST- 2020/07/10 06:00 [entrez]
AID - 10.1021/acs.jproteome.0c00219 [doi]
PST - ppublish
SO  - J Proteome Res. 2020 Aug 7;19(8):3302-3314. doi: 10.1021/acs.jproteome.0c00219. 
      Epub 2020 Jul 24.