PNAS：美国科学家发现导致高原缺氧的相关基因

美国加州大学圣地亚哥分校一项研究提供了对此前发现的埃塞俄比亚高地人对氧浓度低的遗传适应的一个可能的解释。对生活在低氧条件下的埃塞俄比亚高地人的全基因组分析已经找到了与适应缺氧有联系的基因。Gabriel Haddad及其同事测试了其中的一个基因产物内皮素受体B(EDNRB)在适应高海拔方面的作用，这是一种涉及心脏功能的信号传导受体。这组作者在这些高地人的基因组包含内皮素受体B(EDNRB)的区域中识别出了几个核苷酸碱基变化，被包含的序列此前被识别为与心脏功能有关的基因开关的结合位点。当暴露在温和或者极端的缺氧中的时候，只有一份功能正常的内皮素受体B(EDNRB)基因拷贝的经过改造的小鼠比野生型小鼠表现出了更好的心脏功能和关键器官的充氧作用。基因表达分析识别出了在野生型小鼠和突变小鼠中得到反相调控的几个基因。在这些基因中，发现3个基因——Nppa、Sln和Myl4——涉及了与钙调控、心脏收缩和血液循环有关的细胞路径，这很可能解释了突变小鼠在严重缺氧条件下更好的心脏功能。因此，这组作者提出，降低内皮素受体B(EDNRB)的水平有助于在温和到严重缺氧条件下保存心脏功能，不仅在高海拔地区，在海平面条件下也是如此。这组作者说，这些发现解释了内皮素受体B(EDNRB)如何调控对高海拔的适应，并且识别出了这种受体是涉及缺氧的症状的一种可能的治疗靶标。

原文链接：

Endothelin receptor B, a candidate gene from human studies at high altitude, improves cardiac tolerance to hypoxia in genetically engineered heterozygote mice

原文摘要：

To better understand human adaptation to stress, and in particular to hypoxia, we took advantage of one of nature’s experiments at high altitude (HA) and studied Ethiopians, a population that is well-adapted to HA hypoxic stress. Using whole-genome sequencing, we discovered that EDNRB (Endothelin receptor type B) is a candidate gene involved in HA adaptation. To test whether EDNRB plays a critical role in hypoxia tolerance and adaptation, we generated EdnrB knockout mice and found that when EdnrB−/+ heterozygote mice are treated with lower levels of oxygen (O2), they tolerate various levels of hypoxia (even extreme hypoxia, e.g., 5% O2) very well. For example, they maintain ejection fraction, cardiac contractility, and cardiac output in severe hypoxia. Furthermore, O2 delivery to vital organs was significantly higher and blood lactate was lower in EdnrB−/+ compared with wild type in hypoxia. Tissue hypoxia in brain, heart, and kidney was lower inEdnrB−/+ mice as well. These data demonstrate that a lower level of EDNRB significantly improves cardiac performance and tissue perfusion under various levels of hypoxia. Transcriptomic profiling of left ventricles revealed three specific genes [natriuretic peptide type A (Nppa), sarcolipin (Sln), and myosin light polypeptide 4 (Myl4)] that were oppositely expressed (q < 0.05) between EdnrB−/+ and wild type. functions related to these gene networks were consistent with a better cardiac contractility and performance. We conclude that EDNRB plays a key role in hypoxia tolerance and that a lower level of EDNRB contributes, at least in part, to HA adaptation in humans.

doi: 10.1073/PNAS.1507486112

作者：Tsering Stobdan