Blunted nitric oxide regulation in Tibetans under high-altitude hypoxia

作者：Yaoxi He, Xuebin Qi, Ouzhuluobu, Shiming Liu, Jun Li, Hui Zhang, Baimakangzhuo, Caijuan Bai, Wangshan Zheng, Y. Guo, Duojizhuoma, Baimayangji, Dejiquzong, Bianba, Gonggalanzi, Yongyue Pan, Qula, Kangmin, Cirenyangji, Wei Guo, Yangla, Yi Peng, Xiaoming Zhang, Kun Xiang, Zhaohui Yang, Liangbang Wang, Gengdeng Gengdeng, Yanfeng Zhang, Tianyi Wu, Bing Su, Chaoying Cui · 发表于：National Science Review · 年份：2018 · DOI：10.1093/nsr/nwy037 · 被引用次数：69 · 研究领域：High Altitude and Hypoxia、Neuroscience of respiration and sleep、Eicosanoids and Hypertension Pharmacology

ABSTRACT 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 upregulatio...