Blunted nitric oxide regulation in Tibetans under high-altitude hypoxia
| Autor: | Xuebin Qi, Yi Peng, Kun Xiang, Dejiquzong, Yongbo Guo, Tianyi Wu, Zhaohui Yang, Baimayangji, Baimakangzhuo, Jun Li, Yongyue Pan, Wangshan Zheng, Wei Guo, Qula, Yanfeng Zhang, Gonggalanzi, Ouzhuluobu, Caijuan Bai, Xiaoming Zhang, Cirenyangji, Liangbang Wang, Hui Zhang, Yaoxi He, Bing Su, Gengdeng, Duojizhuoma, Kangmin, Chaoying Cui, Bianba, Shiming Liu, Yangla |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Multidisciplinary biology High altitude hypoxia Effects of high altitude on humans biology.organism_classification Umbilical vein Nitric oxide 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine Endocrinology chemistry Downregulation and upregulation Enos Internal medicine medicine 030217 neurology & neurosurgery Gene knockout Vasomotor tone |
| Zdroj: | National Science Review. 5:516-529 |
| ISSN: | 2053-714X 2095-5138 |
| Popis: | Nitric oxide (NO) is an important molecule for vasomotor tone, and elevated NO signaling was previously hypothesized as a unique and adaptive physiological change in highland Tibetans. However, there has been lack of NO data from Tibetans living at low altitude and lowlander immigrants living at high altitude, which is crucial to test this hypothesis. Here, through cross-altitude (1990–5018 m) and cross-population (Tibetans and Han Chinese) analyses of serum NO metabolites (NOx) of 2086 individuals, we demonstrate that although Tibetans have a higher serum NOx level compared to lowlanders, Han Chinese immigrants living at high altitude show an even higher level than Tibetans. Consequently, our data contradict the previous proposal of increased NO signaling as the unique adaptive strategy in Tibetans. Instead, Tibetans have a relatively lower circulating NOx level at high altitude. This observation is further supported by data from the hypoxic experiments using human umbilical vein endothelial cells and gene knockout mice. No difference is detected between Tibetans and Han Chinese for endothelial nitric oxide synthase (eNOS), the key enzyme for circulating NO synthesis, suggesting that eNOS itself is unlikely to be the cause. We show that other NO synthesis-related genes (e.g. GCH1) carry Tibetan-enriched mutations significantly associated with the level of circulating NOx in Tibetans. Furthermore, gene network analysis revealed that the downregulation and upregulation of NOx is possibly achieved through distinct pathways. Collectively, our findings provide novel insights into the physiological and genetic mechanisms of the evolutionary adaptation of Tibetans to high-altitude hypoxia. |
| Databáze: | OpenAIRE |
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