肾去交感神经术抑制TLR4/NF-κB信号通路介导的心-脑共同炎症反应与心肌纤维化

There is a specific cardio-cerebral inflammatory response in myocardial injury. Excessive, sustained and expanded of inflammation can promote myocardial fibrosis. Both of clinical and experimental studies demonstrate that renal denervation (RDN) could inhibit myocardial fibrosis. However, the underlying mechanisms remain unclear. Our previous studies have shown that RDN can significantly reduce atrial and ventricular myocardial fibrosis and systemic inflammatory response in rats underwent transverse aortic constriction (TAC). TLR4/NF-κB signaling pathway is closely related to inflammation. Hence, we assume that the ability of RDN inhibiting TLR4/NF-κB signaling pathway is responsible for the improvements of cardio-cerebral inflammation and myocardial fibrosis. In a mouse model of TAC-induced cardiomyopathy, we will detect the expression levels of TLR4/NF-κB signaling pathway components and related inflammation factors. In order to further determine whether the effects of RDN on cardio-cerebral inflammatory is related to TLR4/NF-κB signaling pathway, we are going to adopt TLR4 knock-out mice. Meanwhile, 18F-FDG-PET imaging and molecular biology will be used, with aims to explore the underlying mechanisms of RDN for improving myocardial fibrosis and ventricular remodeling, at molecular, genetic, organic and intact level. It will provide a theoretical basis for the treatment of heart failure by RDN.

心肌损伤时存在特异性的心-脑共同炎症反应，过度、持续和扩大的炎症反应能够促进心肌纤维化。临床和基础研究均发现肾去交感神经术(RDN)可抑制心肌纤维化，但机制不清楚。课题组前期研究发现RDN明显降低TAC心衰大鼠心房心室纤维化程度以及血浆炎症因子水平，而TLR4/NF-κB信号通路与炎症密切相关，由此，我们推测RDN可通过调控TLR4/NF-κB信号通路抑制心-脑共同炎症反应以及心肌纤维化。本研究在建立TAC心衰小鼠模型基础上，检测RDN对 TLR4/NF-κB 信号通路表达或活化水平的影响；并通过敲除TLR4基因，分析RDN是否通过TLR4/NF-κB信号通路抑制心-脑共同炎症反应；同时利用18F-FDG-PET炎症显像与分子生物学技术，从分子、基因、器官和整体水平探讨RDN抑制心肌纤维化的机制，为RDN治疗心衰提供理论依据。

心梗后出现的中枢神经炎症会促进多种脑组织并发症的进展，不仅极大增加了社会负担，目前也尚无有效的治疗方法。通过本课题的研究，我们发现：①心梗后肠道屏障损伤促进肠道菌群代谢产物LPS入血，并会进一步促进中枢神经炎症反应的发生；②TLR4相关通路是心梗后肠道-血液LPS易位发挥促炎作用的重要通路；③RDN可改善心梗后肠道菌群失调与肠道屏障功能，从而改善肠道-血液LPS易位，进而缓解中枢神经炎症。综上，通过本课题的研究，我们从肠脑轴的角度阐明了心梗后中枢神经炎症发生发展的机制，并在此基础上进一步探究了RDN对心梗后中枢神经炎症的保护作用，为改善心血管疾病中的脑组织并发症提供了新的治疗策略。