<i>GCH1</i> contributes to high-altitude adaptation in Tibetans by regulating blood nitric oxide

Yongbo Guo; Wangshan Zheng; Tian Yue; Baimakangzhuo; Xuebin Qi; Kai Liu; Liya Li; Yaoxi He; Bing Su

doi:10.1016/j.jgg.2025.04.005

GCH1 contributes to high-altitude adaptation in Tibetans by regulating blood nitric oxide

doi: 10.1016/j.jgg.2025.04.005

Yongbo Guo^a,b,
Wangshan Zheng^a,b,c,
Tian Yue^a,b,
Baimakangzhuo^d,
Xuebin Qi^e,
Kai Liu^a,
Liya Li^a,
Yaoxi He^a, ,,
Bing Su^a,f, ,

a. State Key Laboratory of Genetic Evolution and Animal Models, and Yunnan Key Laboratory of Integrative Anthropology, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China;
b. Kunming College of Life Science, University of Chinese Academy of Sciences, Beijing 100101, China;
c. School of Biological and Pharmaceutical Engineering, Lanzhou Jiaotong University, Lanzhou, Gansu 730070, China;
d. High Altitude Medical Research Center, School of Medicine, Tibetan University, Lhasa, Xizang 850000, China;
e. State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, Yunnan 650223, China;
f. Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, Yunnan 650223, China

基金项目:

32170632 and 32000390 to Y.H.

32400503 to Y.G.), Major Scientific Project of Yunnan Province (202305AH340007 to B.S.), Yunnan Revitalization Talent Support Program Science & Technology Champion Project (202005AB160004 to B.S.), Yunnan Revitalization Talent Support Program Innovation Team (202405AS350008), Yunnan Scientist Workshops (to B.S.), the Youth Innovation Promotion Association of CAS (to Y.H.), the Science and Technology General Program of Yunnan Province (202301AW070010 and 202001AT070110 to Y.H.), and the Provincial Key Research, Development, and Translational Program (XZ202101ZY0009G to Baima.).

We are grateful to all participants in this study. We would like to express our gratitude to GemPharmatech Co., Ltd, Jiangsu, China, for their completion of the gene-edited mouse model production. This study was funded by grants from the National Natural Science Foundation of China (32288101 and 91631306 to B.S

详细信息

通讯作者:
Yaoxi He,E-mail:heyaoxi@mail.kiz.ac.cn

Bing Su,E-mail:sub@mail.kiz.ac.cn

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出版历程
- 收稿日期: 2024-10-11
- 录用日期: 2025-04-09
- 修回日期: 2025-04-07
- 网络出版日期: 2025-07-11

GCH1 contributes to high-altitude adaptation in Tibetans by regulating blood nitric oxide

Yongbo Guo^a,b,
Wangshan Zheng^a,b,c,
Tian Yue^a,b,
Baimakangzhuo^d,
Xuebin Qi^e,
Kai Liu^a,
Liya Li^a,
Yaoxi He^{a
, ,},
Bing Su^{a,f
, ,}

a. State Key Laboratory of Genetic Evolution and Animal Models, and Yunnan Key Laboratory of Integrative Anthropology, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China;
b. Kunming College of Life Science, University of Chinese Academy of Sciences, Beijing 100101, China;
c. School of Biological and Pharmaceutical Engineering, Lanzhou Jiaotong University, Lanzhou, Gansu 730070, China;
d. High Altitude Medical Research Center, School of Medicine, Tibetan University, Lhasa, Xizang 850000, China;
e. State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, Yunnan 650223, China;
f. Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, Yunnan 650223, China

Funds:

32170632 and 32000390 to Y.H.

摘要

摘要:
Nitric oxide (NO) is a key vasodilator that regulates vascular pressure and blood flow. Tibetans have developed a “blunted” mechanism for regulating NO levels at high altitude, with GTP cyclohydrolase 1 (GCH1) identified as a key candidate gene. Here, we present comprehensive genetic and functional analyses of GCH1, which exhibits strong Darwinian positive selection in Tibetans. We show that Tibetan-enriched GCH1 variants down-regulate its expression in the blood of Tibetans. Based on this observation, we generate the heterozygous Gch1 knockout (Gch1⁺^/^–) mouse model to simulate its downregulation in Tibetans. We find that under prolonged hypoxia, the Gch1⁺^/^– mice have relatively higher blood NO and blood oxygen saturation levels compared with the wild-type (WT) controls, providing better oxygen supplies to the cardiovascular and pulmonary systems. Markedly, hypoxia-induced cardiac hypertrophy and pulmonary remodeling are significantly attenuated in the Gch1⁺^/^– mice compared with the WT controls, likely due to the adaptive changes in molecular regulations related to metabolism, inflammation, circadian rhythm, extracellular matrix, and oxidative stress. This study sheds light on the role of GCH1 in regulating blood NO, contributing to the physiological adaptation of the cardiovascular and pulmonary systems in Tibetans at high altitude.
- GCH1 /
- Nitric oxide /
- Tibetans /
- High altitude /
- Hypoxia /
- Adaptation
Abstract:
Nitric oxide (NO) is a key vasodilator that regulates vascular pressure and blood flow. Tibetans have developed a “blunted” mechanism for regulating NO levels at high altitude, with GTP cyclohydrolase 1 (GCH1) identified as a key candidate gene. Here, we present comprehensive genetic and functional analyses of GCH1, which exhibits strong Darwinian positive selection in Tibetans. We show that Tibetan-enriched GCH1 variants down-regulate its expression in the blood of Tibetans. Based on this observation, we generate the heterozygous Gch1 knockout (Gch1⁺^/^–) mouse model to simulate its downregulation in Tibetans. We find that under prolonged hypoxia, the Gch1⁺^/^– mice have relatively higher blood NO and blood oxygen saturation levels compared with the wild-type (WT) controls, providing better oxygen supplies to the cardiovascular and pulmonary systems. Markedly, hypoxia-induced cardiac hypertrophy and pulmonary remodeling are significantly attenuated in the Gch1⁺^/^– mice compared with the WT controls, likely due to the adaptive changes in molecular regulations related to metabolism, inflammation, circadian rhythm, extracellular matrix, and oxidative stress. This study sheds light on the role of GCH1 in regulating blood NO, contributing to the physiological adaptation of the cardiovascular and pulmonary systems in Tibetans at high altitude.
- GCH1 /
- Nitric oxide /
- Tibetans /
- High altitude /
- Hypoxia /
- Adaptation

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GCH1 contributes to high-altitude adaptation in Tibetans by regulating blood nitric oxide

doi: 10.1016/j.jgg.2025.04.005

通讯作者:
Yaoxi He,E-mail:heyaoxi@mail.kiz.ac.cn

Bing Su,E-mail:sub@mail.kiz.ac.cn

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GCH1 contributes to high-altitude adaptation in Tibetans by regulating blood nitric oxide

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GCH1 contributes to high-altitude adaptation in Tibetans by regulating blood nitric oxide

doi: 10.1016/j.jgg.2025.04.005

通讯作者: Yaoxi He,E-mail:heyaoxi@mail.kiz.ac.cn Bing Su,E-mail:sub@mail.kiz.ac.cn

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GCH1 contributes to high-altitude adaptation in Tibetans by regulating blood nitric oxide

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出版历程

目录

通讯作者:
Yaoxi He,E-mail:heyaoxi@mail.kiz.ac.cn

Bing Su,E-mail:sub@mail.kiz.ac.cn