去肾交感神经治疗心力衰竭的神经和体液调控机制研究

Heart failure is the end stage of a myriad of cardiovascular diseases. Antagonizing the excessive activation of the sympathetic nervous system (SNS) is an important part of treating heart failure. Our previous studies have confirmed that renal denervation (RD) can inhibit SNS activity and improve cardiac function in rats, but its mechanism remains unclear. We propose that the paraventricular nucleus (PVN) is a key target for inhibiting the increased activity of the SNS, while miRNA exosomes may be a novel target for inhibition of SNS activity through RD, with the two may have an effect on each other. To test this hypothesis, we will create a rat model with overactivation of SNS in post-myocardial infarction heart failure, and use RD to block the afferent projection effects and investigate the changes of PVN and its mechanisms. At the same time, cardiac and renal sources of miRNA exosomes before and after RD will be quantitatively analyzed to evaluate its significance as an indicator RD efficacy in the treatment of heart failure and as a potential target for intervention. This study will confirm the exact mechanisms of RD, not only shedding any connotations of a placebo effect of RD, but will explore specific indicators for monitoring its efficacy. This in turn provides a more solid theoretical and experimental basis for the clinical use of RD in the treatment of heart failure.

心力衰竭是各种心血管疾病的终末阶段，拮抗交感神经系统（SNS）过度激活是心衰治疗的重要手段。我们的前期研究证实了去肾脏交感神经（RD）可以抑制心衰大鼠SNS活动并改善心功能，但RD抑制SNS活动的机制至今不明。结合前期研究及当前进展，我们提出科学假说：下丘脑室旁核（PVN）是RD阻断SNS神经调控通路的关键靶点，miRNA外泌体则可能是全新的RD体液调控通路的关键靶点，二者存在相互协调作用。为此，我们拟利用大鼠建立心梗后SNS过度激活心衰模型，通过RD阻断传入神经通路的中枢投射效应，研究PVN的变化及神经机制；同时定量分析心、肾来源miRNA外泌体在RD前后的变化，评估其作为RD治疗心衰疗效监测指标的意义以及作为潜在独立干预靶点的可能。本研究将证实RD确切的疗效机制，不仅使RD摆脱安慰剂效应的阴影，还将探索特异的疗效监测指标，为RD成为临床上全新的心衰治疗方式提供坚实实验和理论基础。

心力衰竭是各种心血管疾病的终末阶段，拮抗交感神经系统（SNS）过度激活是心衰治疗的重要手段。我们的前期研究证实了去肾脏交感神经（RD）可以抑制心衰大鼠SNS活动并改善心功能，但RD抑制SNS活动的机制至今不明。结合前期研究及当前进展，我们提出科学假说：下丘脑室旁核（PVN）是RD阻断SNS神经调控通路的关键靶点，miRNA外泌体则可能是全新的RD体液调控通路的关键靶点，二者存在相互协调作用。.本研究首先通过构建急性心肌梗死后心衰大鼠模型，分别在急性心肌梗死后心衰后1天、4周对其进行不同时间的去肾神经干预或药物治疗（ARB+β-Block），发现RDN改善心衰的作用强于ARB+β-Block联合治疗。通过对大鼠血浆肾素、Ang Ⅱ、ALD 、NE水平分析，发现RDN具有降低心梗后心衰大鼠交感神经系统及RAAS系统活性的作用。通过对大鼠心电的分析，发现RDN具有调节心脏交感-迷走神经功能平衡的作用。通过分离大鼠血浆外泌体，测定血浆外泌体miRNA,发现miRNA-21与miRNA-22可能参与RDN治疗心梗后心衰的调控机制。本研究证实了RD的疗效机制，探索了以循环外泌体miRNA作为疗效监测指标的可行性，为RD成为临床上全新的心衰治疗方式提供坚实实验和理论基础。