Blunted Nitric Oxide Regulation in Tibetans under High Altitude Hypoxia

Yaoxi He, Xuebin Qi, Ouzhuluobu NA, Shiming Liu, Jun Li, Hui Zhang, Baimakangzhuo NA, Caijuan Bai, Wangshan Zheng, Yongbo Guo, Duojizhuoma NA, Baimayangji NA, Dejiquzong NA, Bianba NA, Gonggalanzi NA, Yongyue Pan, Qula NA, Kangmin NA, Cirenyangji NA, Wei Guo, Yangla NA, Yi Peng, Xiaoming Zhang, Kun Xiang, Zhaohui Yang, Liangbang Wang, Gengdeng NA, Yanfeng Zhang, Tianyi Wu, Bing Su, Chaoying Cui

Index: 10.1093/nsr/nwy037

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Abstract

Nitric oxide (NO) is an important molecule for vasomotor tone, and an 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 are crucial to test this hypothesis. Here through cross-altitude (1,990m-5,018 m) and cross-population (Tibetans and Han Chinese) analyses of serum NO metabolites (NOx) of 2,086 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 an 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 eNOS, the key enzyme for circulating NO synthesis, suggesting that eNOS itself is unlikely 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 reveal that the downregulation and the upregulation of NOx are possibly 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.