Angiotensin II-dependent hypertension requires cyclooxygenase 1-derived prostaglandin E2 and EP1 receptor signaling in the subfornical organ of the brain.
Angiotensin II-dependent hypertension requires cyclooxygenase 1-derived prostaglandin E2 and EP1 receptor signaling in the subfornical organ of the brain.
复制标题
血管紧张素II依赖性高血压需要大脑副脱机器官中的环氧酶1衍生的前列腺素E2和EP1受体信号传导。
DOI：
10.1161/hypertensionaha.111.182071
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发表时间：
2012-04
期刊：
影响因子：
--
通讯作者：
Davisson RL
中科院分区：
文献类型：
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作者：
Cao X;Peterson JR;Wang G;Anrather J;Young CN;Guruju MR;Burmeister MA;Iadecola C;Davisson RL
环氧合酶（考克斯）衍生的前列腺素类化合物长期以来一直参与血压（BP）调节。最近，前列腺素E2（PGE 2）及其受体EP 1 R已成为血管紧张素II（Ang-II）依赖性高血压（HTN）和相关终末器官损害的关键参与者。然而，PGE 2的酶来源，即考克斯-1或考克斯-2，及其作用位点尚不清楚。穹窿下器官（SFO）是通过活性氧（ROS）介导系统性Ang-II依赖性HTN的关键前脑区域。我们测试了SFO中PGE 2/EP 1 R和ROS信号传导之间的串扰是Ang-II HTN所需的假设。BP的放射性遥测评估显示，在EP 1 R或考克斯-1无效突变但考克斯-2无效突变的小鼠中，全身输注“慢升压”剂量的Ang-II诱导的HTN被消除。当将EP 1 R拮抗剂SC-51089直接注入野生型小鼠脑中时，SFO中慢升压Ang-II诱导的HTN和ROS形成被阻止，并且Ang-II诱导的ROS产生在EP 1 R −/−和考克斯-1−/−的SFO中的细胞中被钝化，但在考克斯-2−/−小鼠中则没有。此外，慢升压Ang-II输注导致SFO中PGE 2水平增加约3倍，但在其他脑区则没有。最后，在EP 1 R缺失小鼠的SFO中选择性地进行EP 1 R的遗传重建足以拯救该模型的SFO中慢升压AngII引起的HTN和ROS形成。因此，考克斯-1衍生的PGE 2信号通过EP 1 R在SFO是必需的ROS介导的HTN由全身输注Ang-II诱导，并表明，EP 1 R在SFO可能提供一个新的抗高血压治疗的目标。
Cyclooxygenase (COX)-derived prostanoids have long been implicated in blood pressure (BP) regulation. Recently prostaglandin E2 (PGE2) and its receptor EP1R have emerged as key players in angiotensin II (Ang-II)-dependent hypertension (HTN) and related end-organ damage. However, the enzymatic source of PGE2, ie COX-1 or COX-2, and its site(s) of action are not known. The subfornical organ (SFO) is a key forebrain region that mediates systemic Ang-II-dependent HTN via reactive oxygen species (ROS). We tested the hypothesis that cross-talk between PGE2/EP1R and ROS signaling in the SFO is required for Ang-II HTN. Radiotelemetric assessment of BP revealed that HTN induced by infusion of systemic “slow-pressor” doses of Ang-II was abolished in mice with null mutations in EP1R or COX-1 but not COX-2. Slow-pressor Ang-II-evoked HTN and ROS formation in the SFO were prevented when the EP1R antagonist SC-51089 was infused directly into brains of wild-type mice, and Ang-II-induced ROS production was blunted in cells dissociated from SFO of EP1R−/− and COX-1−/− but not COX-2−/− mice. In addition, slow-pressor Ang-II infusion caused a ~3-fold increase in PGE2 levels in the SFO but not in other brain regions. Finally, genetic reconstitution of EP1R selectively in the SFO of EP1R-null mice was sufficient to rescue slow-pressor AngII-elicited HTN and ROS formation in the SFO of this model. Thus, COX-1-derived PGE2 signaling through EP1R in the SFO is required for the ROS-mediated HTN induced by systemic infusion of Ang-II, and suggests that EP1R in the SFO may provide a novel target for antihypertensive therapy.