Blunted nitric oxide regulation in Tibetans under high-altitude hypoxia
Blunted nitric oxide regulation in Tibetans under high-altitude hypoxia
复制标题
高原缺氧下藏族一氧化氮调节减弱
DOI：
10.1093/nsr/nwy037
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发表时间：
2018-07-01
影响因子：
20.6
通讯作者：
Cui, Chaoying
中科院分区：
文献类型：
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作者：
He, Yaoxi;Qi, Xuebin;Cui, Chaoying
一氧化氮（NO）是血管舒张张张力的重要分子，并且以前没有信号被认为是高地藏族的独特和适应性生理变化。但是，没有居住在低海拔的藏人和生活在高海拔的低地移民的数据，这对于检验这一假设至关重要。在这里，通过跨峰（1990-5018 m）和跨种群（藏族和汉族中国人）对2086个人的血清无代谢物（NOX）的分析，我们证明，尽管藏族具有更高的低地移民，但汉族中国移民的居民比藏人更高。因此，我们的数据与先前没有信号的提议相矛盾，因为藏族中的独特自适应策略。取而代之的是，藏人在高海拔地区具有相对较低的循环NOx水平。使用人脐静脉内皮细胞和基因基因敲除小鼠，来自低氧实验的数据进一步支持了这一观察结果。对于内皮一氧化氮合酶（ENOS），藏族和汉族之间未检测到差异，这是循环无合成的关键酶，这表明ENOS本身不太可能是原因。我们表明，其他无合成相关的基因（例如GCH1）携带藏族富集的突变与藏族中循环NOX的水平显着相关。此外，基因网络分析表明，NOX的下调和上调可能通过不同的途径实现。总的来说，我们的发现提供了对藏族对高空缺氧进化适应的生理和遗传机制的新见解。
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.