室旁核小电导钙激活钾通道调控盐敏感性高血压交感神经活动及机制

Salt-sensitive hypertension (SSH) is a common disease with high morbility and wide impact on public health. It is widely accepted that SSH may lead to severe heart, brain, kidney deseases. However, the pathogenesis of SSH is unclear and thus receives extensive studies. Previous studies have suggested that the enhancement of sympathetic nerve activity is a patho-physiological basis for SSH. However, the cellular and molecular mechanism for enhanced sympathetic activity and SSH is unclear. Small conductance Ca2+-activated K+ channels (SK) in paraventricular nucleus of hypothalamus (PVN) and play important role in neuroendocrine and central control of sympathetic activity and arterial blood pressure. Our pilot studies revealed that the angiotensin type 1 receptor (AT1R) and calcium/calmodulin kinase II (CaMKII) expression are upregulated, however, the expression of SK in PVN was decreased in a rat SSH model, resulting in enhancing of activity or excitability of RVLM projecting PVN neurons (PVN-RVLM), suggesting AT1R/CaMKII/SK is one of the key components/signal pathway which link sympathetic drive and cardiovascular disturbance such as hypertension. In this study, we will use a rat SSH model induced by high-salt diet and chronic infusion of angiotensin II to investigate the mechanism underlying increased sympathetic nerve activity in SSH. We will performed a series of experiments in molecular, cellular, organism, and overall levels to test our hypotheses. This project intends to elucidate the mechanism by which inhibition and/or downregulation of SK exacerbates SSH by increasing sympathetic activity. It will provides new tactics for clinical prevention and treatment of SSH.

盐敏感性高血压(SSH）发病率高，可引起严重的心、脑、肾疾病。研究提示交感神经活性增强是SSH发病的共同病理生理基础，亦是目前的研究热点。然而，对于SSH中交感神经活性增强的细胞及分子机制仍不清楚。下丘脑室旁核（PVN）和下丘脑小电导钙激活钾通道（SK）在机体神经内分泌和交感神经活动及动脉血压的调控中起重要作用。我们前期研究显示，SSH大鼠下丘脑PVN中血管紧张素II受体I（AT1R）和 钙调磷酸激酶II（CaMKII）表达上调，SK通道功能下调进而导致PVN投射至RVLM的自主神经元动作电位发放频率增强，提示下丘脑PVN内 AT1R/CaMKII/SK 信号通路是连接交感神经活性增强及高血压的重要纽带。本研究拟采用高盐饮食兼皮下注射血管紧张素II诱导的SSH大鼠模型，通过整体、细胞和分子水平的系列研究，探讨SK通道在SSH中交感神经过度兴奋中的作用机制，为临床SSH的防治提供新策略。

心血管疾病主要包括高血压、冠心病、充血性心力衰竭等。目前，心血管疾病仍然是人类生命的头号杀手。全世界每年有一千七百万人死于心血管疾病。毫无疑问，预防和治疗心血管疾病是医学与生物学的重大任务。交感神经系统过度激活在盐敏感性高血压（SSH）的发生、发展和并发症形成中起了极其重要的作用。药物阻滞、射频消融或切除交感神经导致多种副作用和并发症，疗效欠佳。迄今SSH交感神经兴奋亢进机制不详。本项目从SSH的交感神经活动过度激活机制这一关键问题入手，应用多种先进研究方法，从整体、脑片、细胞和分子基因水平综合研究下丘脑室旁核(PVN)内ANGII/AT1R/CaMKII/SK2信号通路介导SSH交感神经过度激活的分子机制。本项目的研究结果首次揭示了机体SSH时下丘脑室旁核ANGII、AT1R、CaMKII基因和SK2蛋白表达的负性相关变化规律；首次阐明了ANGII、AT1R、CaMKII和SK2分别是机体SSH时心血管中枢整合作用失衡的重要内源性抗病和致病基因的机制；锁定了血浆内NE和AVP水平升高是SSH发病的早期预警分子。首次证实了SSH时PVN内ANGII、AT1R和CaMKII功能和/或表达上调诱发中枢整合作用关键分子SK2表达下调，从而导致交感神经激活，最终恶化SSH的假说。首次明确了下丘脑PVN内ANGII为SSH发病始动因子，首次确证了SSH状态下PVN内ANGII/AT1R/CaMKII/SK2信号网络体系。本课题从新的视角成功阐明了SSH发生的分子机制，并为SSH的防治提供新靶点。