Cardiac-specific knockout and pharmacological inhibition of Endothelin receptor type B lead to cardiac resistance to extreme hypoxia.
Cardiac-specific knockout and pharmacological inhibition of Endothelin receptor type B lead to cardiac resistance to extreme hypoxia.
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DOI：
10.1007/s00109-018-1673-2
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发表时间：
2018-09
期刊：
影响因子：
--
通讯作者：
Haddad GG
中科院分区：
文献类型：
--
作者：
Stobdan T;Zhou D;Williams AT;Cabrales P;Haddad GG
氧在心脏能量代谢中起着核心作用。在高海拔低氧环境下，EDNRB与人体低氧适应有关。我们随后在全杂合基因敲除小鼠（Ednrb+/−）中的研究表明，当暴露于极端缺氧时，这些小鼠的心脏功能是保守的。本研究的主要目标是：i）确定心肌细胞EdnrB在缺氧应激下维持心脏功能的功能作用; ii）验证我们使用EDNRB阻断剂在Ednrb+/−小鼠中检测到的表型。与整体敲除不同，心脏特异性杂合子（EdnrBflox/+）和纯合子（EdnrBflox/flox）EdnrB敲除小鼠表型正常。当用分级低水平的氧（10%和5%O2）处理时，EdnrBflox/+和EdnrBflox/flox都是耐缺氧的。与cre阴性对照组相比，EdnrBflox/+组在10%和5%O2下的心脏指数显著更高，乳酸水平显著更低（P<0.05）。同时，与对照小鼠相比，用BQ-788（EDNRB特异性）处理的小鼠具有显著更高的心脏指数（P<0.005）和显著更低的乳酸水平（P<0.0001）。用波生坦处理的小鼠获得了类似的结果（非特异性）。这些数据表明，心肌细胞中EdnrB的较低水平或完全缺乏显著改善了极端缺氧下的心脏性能，这是心肌细胞EdnrB在调节心脏功能中的一种新作用。此外，在极端缺氧下的这种拯救也可以使用EDNRB特异性药理学试剂来实现，BQ-788这系统地证实了，在遗传学和生物学上，在极端缺氧胁迫下较低的EDNRB的保护作用。
Oxygen plays a central role in cardiac energy metabolism. At high-altitude where the ambient oxygen level is low, we found EDNRB is associated with human hypoxia adaptation. Our subsequent study in global heterozygous knockout mice (Ednrb+/−) revealed that cardiac function was conserved in these mice when exposed to extreme hypoxia. The major goal of this study was i) to determine the functional role of cardiomyocyte EdnrB in maintaining cardiac function under hypoxic stress and ii) to validate the phenotypes we detected in Ednrb+/− mice using EDNRB blockers. Unlike the global knockouts, cardiac specific heterozygote (EdnrBflox/+) and homozygote (EdnrBflox/flox) EdnrB knockout mice were phenotypically normal. When treated with graded low levels of oxygen (10% and 5% O2), both EdnrBflox/+ and EdnrBflox/flox were hypoxia tolerant. The cardiac-index at 10% and 5% O2 for EdnrBflox/+ were significantly higher and lactate levels were significantly lower when compared to the cre-negative controls (P<0.05). Simultaneously, mice treated with BQ-788 (EDNRB specific) had a significantly higher cardiac-index (P<0.005) and significantly lower lactate levels (P<0.0001) than in control mice. A similar result was obtained with mice treated with Bosentan (non-specific). These data indicate that a lower level or complete lack of EdnrB in the cardiomyocytes significantly improves cardiac performance under extreme hypoxia, a novel role of cardiomyocyte EdnrB in the regulation of cardiac function. Furthermore, this rescue under extreme hypoxia can also be achieved using EDNRB specific pharmacological agents e.g., BQ-788. This systematically confirms, both genetically and pharmacologically, the protective role of a lower EDNRB under extreme hypoxia stress.
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