AT2受体调控主动脉压力反射的新靶点-Nav1.9通道

AT2受体（AT2R）在女性组织中高表达，是女性一种心脏和血管潜在的保护型受体。最新研究表明结状神经节内髓鞘化Ah-型压力感受器神经元（Ah-BRN）是仅存在于雌性大鼠的神经元亚型，其以独特的生理特性参与主动脉压力反射。申请人初步证实相比雄性，雌性大鼠结状神经节高度表达AT2R，单细胞RT-PCR结果显示其主要表达于Ah-BRN。本课题将深入研究AT2受体如何调节主动脉压力反射及其分子机制。实验拟用细胞转染，膜片钳及分子生物学等方法证实AT2R激活可通过增加Nav1.9通道表达提高雌鼠压力感受器敏感性而增强主动脉压力反射，使其血压维持在较低水平。并研究MAPK信号通路和miR-145/miR-485参与AT2受体调控Nav1.9通道的调节机制。本研究结果将从传入神经调控机制入手揭示血压调节的性别差异，对心血管疾病合理地诊断、治疗和预后评估有重大科学意义。

AT2R is the receptor that highly expresses in heart and kidney of females and plays a potential role in heart and blood vessle protection to counteract to AT1 receptor compared with male. Our recent study showed a gender-specific subpopulation of myelianted Ah-type baroreceptor neuron (Ah-BRN) distributed in nodose ganglion of female rats, which contributes greatly to baroreceptor reflex because of its electrophysilogical properties, i.e. lower threshold in action potential firings and higher frequency in repetitive discharges responding to afferent signal of blood presure changes rasing from baroreceptor endings located in the aortic wall. As an important modulator of neuronal and humoral regulation system, whether and how AT2R modulate blood pressure through the baroreceptor reflex in female was largely unknown. Our prelimitory data demonstrated a higher AT2R expression in nodose neurons of female rats and this result was strongly supported by the notion of real time RT-PCR from single identified Ah-BRN of female rats, suggesting AT2R may play a key role in baroreflex to make female blood pressure significantly lower than that of males. Our further study attempts to investigate if AT2 receptor in female could modulate baroreceptor reflex through Nav1.9 channel using patch clamp technique, cell transfection, and molecular methods. Our hypothethsis is that AT2R could increase Nav1.9 channel expression and elevate Ah-BRN excitibility which was related with activation of MAPK signaling pathway and down-regulation of miR-145/miR-485 expression. Our project will verify the physiological and clinical significance of AT2R on modulation of blood pressure in female and provide a valuable information for publics and clinicians of how to effiicently menagement of cardiovascular disease and also to guide the development of new drug.