Loss of the aryl hydrocarbon receptor induces hypoxemia, endothelin-1, and systemic hypertension at modest altitude
Loss of the aryl hydrocarbon receptor induces hypoxemia, endothelin-1, and systemic hypertension at modest altitude
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DOI：
10.1161/hypertensionaha.107.100586
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发表时间：
2008-03-01
期刊：
影响因子：
8.3
通讯作者：
Walker, Mary K.
中科院分区：
文献类型：
--
作者：
Lund, Amie K.;Agbor, Larry N.;Walker, Mary K.
芳烃受体 (AHR) 是一种基本的螺旋-环-螺旋 Per-Arnt-Sim 转录因子，介导代谢酶的诱导和某些环境污染物的毒性。尽管 AHR 敲除 (KO) 小鼠出现心脏肥大，但相互矛盾的报道将这种病理与低血压或内皮素 (ET)-1 依赖性高血压联系起来。由于高血压发生在中等海拔地区，我们测试了以下假设：AHR 的丧失会增加对缺氧诱导的 ET-1 的敏感性，从而导致全身性高血压。我们发现AHR KO小鼠在中等海拔（1632 m）时血压升高，但在低海拔（225 m）则血压降低。当居住在海拔 1632 m 的 AHR KO 小鼠暴露于海平面吸入氧分压 (PIO2) 11 天时，血压下降至 225 m 处测量的水平。尽管AHR KO小鼠血浆ET-1在1632 m处显着升高，并在225 m和海平面PIO2处降低，但肺前原ET-1 mRNA在1632 m处显着降低，并在225 m和海平面PIO2处进一步降低。血气分析显示，AHR KO 小鼠在 1632 m 处出现低氧血症、高碳酸血症和酸中毒，这些值分别在海平面 PIO2 下 24 小时和 11 天后减弱和正常化。最后，小干扰 RNA 使内皮细胞中的 AHR 失活显着降低了基础 prepro-ET-1 mRNA，但没有改变缺氧诱导的表达。我们的研究建立了 AHR KO 小鼠模型，其中 PIO2 的适度降低导致低氧血症、血浆 ET-1 增加和全身性高血压，但肺前原 ET-1 mRNA 表达不增加。
The aryl hydrocarbon receptor (AHR) is a basic helix-loop-helix Per-Arnt-Sim transcription factor that mediates induction of metabolic enzymes and toxicity of certain environmental pollutants. Although AHR knockout (KO) mice develop cardiac hypertrophy, conflicting reports associate this pathology with hypotension or endothelin (ET)-1 dependent hypertension. Because hypertension occurred at modest altitude, we tested the hypothesis that loss of AHR increases the sensitivity to hypoxia-induced ET-1, contributing to systemic hypertension. We found that AHR KO mice were hypertensive at modest altitude (1632 m) but hypotensive at low altitude (225 m). When AHR KO mice residing at 1632 m were exposed to the partial pressure of inspired oxygen (PIO2) at sea level for 11 days, blood pressure declined to levels measured at 225 m. Although plasma ET-1 in AHR KO mice was significantly elevated at 1632 m and decreased at 225 m and sea level PIO2, pulmonary prepro-ET-1 mRNA was significantly reduced at 1632 m and decreased further at 225 m and sea level PIO2. Blood gas analysis revealed that AHR KO mice were hypoxemic, hypercapnic, and acidotic at 1632 m, values that were attenuated and normalized after 24 hours and 11 days under sea level PIO2, respectively. Lastly, AHR inactivation in endothelial cells by small interfering RNA significantly reduced basal prepro-ET-1 mRNA but did not alter hypoxia-induced expression. Our studies establish the AHR KO mouse as a model in which modest decreases in PIO2 lead to hypoxemia, increased plasma ET-1, and systemic hypertension without increased pulmonary prepro-ET-1 mRNA expression.