Nogo-B介导的神经再生对肾交感神经射频消融术心衰疗效的影响及机制研究

The effect of renal sympathetic denervation (RSD) on heart failure decreased gradually with time after RSD, suggesting something can affect the roles of RSD. We have reported that the severity of heart failure was associated with renal sympathetic nerve activities and RSD can improve cardiac function. In our preliminary test, the increase of renal sympathetic nerve cells accompanied by worse of cardiac function after RSD, which can be modulated by Nogo-B, was observed. On the basis of these studies, we think that regeneration of renal nerve after RSD can affect the effect of RSD on heart failure, and the effective roles of RSD on heart failure can be improved by inhibiting renal nerve regeneration. To clarity the roles of sympathetic nerve regeneration on heart failure after RSD, cardiac function and renal sympathetic nerve activities will be measured in different time after RSD. The changes of regeneration of renal nerve and the effects of RSD on heart failure will be observed to evaluate the roles of Nogo-B in sympathetic nerve regeneration and the value of inhibiting renal nerve regeneration to ameliorate effect of RSD. In order to investigate the mechanism of regeneration of renal nerve after RSD, the association between the degree of nerve regeneration and the activities of MAPKAPK-2、Nogo-B and NGF will also be assessed in different time after RSD. Our study will identify treatment targets for sympathetic nerve regeneration after RSD, and establish the view that decrease the degree of regeneration can enhance the effect of RSD on heart failure.

肾交感神经射频消融术（RSD）治疗心衰的效果随时间推移逐渐减弱的现象提示RSD心衰疗效受一些因素影响。我们的前期研究证实RSD短期内能改善心功能，此外预实验发现随着RSD术后时间的推移，心衰犬肾动脉交感神经细胞数量又开始逐渐增多从而影响心功能，且这种变化受Nogo-B水平高低的调节。因此，我们提出“RSD术后Nogo-B介导的肾交感神经再生会减弱RSD心衰疗效，而抑制再生能改善其疗效”的观点。我们拟采用神经微电极刺激、记录交感神经活性等方法，获得RSD术后肾交感神经再生存在且能影响RSD心衰疗效的证据，评估通过Nogo-B途径抑制再生能优化RSD心衰疗效的作用。利用体内外实验和慢病毒转染方法，探讨RSD术后MAPKAPK-2、Nogo-B、NGF与肾交感神经再生间关系，揭示RSD后肾交感神经再生的机制。为确立干预RSD后肾交感神经再生的作用靶点，优化RSD心衰疗效提供充分的科学依据。

心力衰竭有着较高的患病率和死亡率，心衰治疗的重点是阻断神经内分泌系统激活，阻断心室重构。肾交感神经消融术（RDN）通过干预肾脏交感神经起到降低全身交感神经活性作用。由于神经内分泌系统激活是心衰最根本的发病机制，因此RDN对心衰应该有效。由于RDN治疗后可能存在肾动脉交感神经的再生，再生的交感神经可能会影响RDN心衰疗效。本课题分别探讨了肾交感神经再生以及通过Nogo-B抑制RDN术后肾交感神经再生对RDN心衰疗效的影响。本研究显示RDN能改善心衰鼠的心功能，心衰经RDN治疗后肾动脉存在肾交感神经再生，再生的神经能再支配肾动脉，Nogo-B是抑制RDN术后肾交感神经再生的重要因子。RDN术后肾交感神经再生对心功能无明显影响，使用Nogo-B类似物抑制RDN后心衰鼠肾交感神经再生未能改善反映心功能的心脏超声指标及血清学指标NT-proBNP水平，且抑制RDN后肾交感神经再生对改善RDN心衰疗效无明显作用。Nogo-B、CGRP、β-NGF途径是调节RDN后心衰鼠肾交感神经再生的重要机制。RDN能纠正心衰造成的肠道微生物群落结构及细菌丰度的紊乱，RDN改善心功能作用也可能与其改善心衰鼠肠道菌群紊乱的作用有关，为RDN通过影响肠道菌群发挥抗心衰作用提供了新思路。RDN后肾交感神经再生或抑制肾交感神经再生均对心衰鼠粪便细菌丰度无明显影响。本研究显示心衰RDN术后肾交感神经再生对RDN心衰疗效无明显影响，抑制RDN后肾交感神经再生未能改善RDN心衰疗效，提示无需关注RDN术后肾交感神经再生情况。