RDN抑制心肌纤维化和室性心律失常机制的研究

Cardiac fibrosis is a common pathway for various myocardial injuries as well as heart failure (HF). Simultaneously, fibrosis of myocardium forms the substrate for ventricular arrhythmia. Previous clinical and experimental studies demonstrated that renal denervation (RDN) could inhibit atrial and ventricular remodeling, and reduce the risk of arrhythmia. The underlying mechanisms, however, remain unclear. Our previous study has shown that RDN can significantly reduce atrial, ventricular and renal fibrosis in rats underwent transverse aortic onstriction (TAC). We also observed a decreasing expression of TGF-β1 in myocardium following RDN. Hence, we assume that the ability of RDN inhibiting TGF-β1 / Smads signal pathway is responsible for the improvements of myocardial fibrosis, cardiac remodeling and ventricular arrhythmia. In a well-established mouse model of TAC-induced cardiomyopathy, we will detect the expression levels of TGF-β1 / Smads pathway components and related fibrogenic factors. In order to further determine whether the effects of RDN on cardiac fibrosis is related to TGF-β1/Smads pathway, we will adopt TGF-β1 inhibitors and Smad2/Smad3 knock-out mice. Meanwhile, Data Sciences International (DSI), electrophysiological programmed stimulation, molecular biology and patch-clamp techniques will be used, with aims to explore.the underlying mechanisms of RDN improving myocardial fibrosis, heart remodeling and ventricular arrhythmia, at molecular, genetic, organic and intact level.

心肌纤维化是各种心肌损伤和心衰的共同通路，也是发生室性心律失常的基质。临床和基础研究发现肾去交感神经术（RDN）可抑制心房心室重构和减少心律失常发生，但机制不清楚。课题组前期研究发现RDN明显降低TAC大鼠心房、心室及肾脏的纤维化程度，由此，我们推测RDN可通过抑制TGF-β1/Smads信号通路降低心肌纤维化程度，抑制心脏重构，减少室性心律失常发生。本研究在已成功建立TAC心肌病小鼠模型基础上，检测TGF-β1/Smads信号通路及相关致纤维化因子表达水平；进一步通过阻断TGF-β1及敲除Smad2、Smad3基因，分析RDN是否通过TGF-β1/Smads信号通路减少心肌纤维化；同时利用植入子、电生理程序刺激、分子生物学及膜片钳等技术，从分子、基因、器官和整体水平探讨RDN减少TAC小鼠心肌纤维化、抑制心脏重构和室性心律失常。为RDN治疗心力衰竭提供理论基础。

心肌纤维化是各种心肌损伤引起心脏重构的共同通路，也为心律失常的发生提供了重要基质。心律失常，尤其是室性心律失常是引起心源性猝死的主要原因，但目前尚无有效的防治策略。前期研究发现RDN可以改善TACiHF和IPiCMP两种模型大鼠心脏功能，明显减少心房、心室纤维化，但是RDN对心律失常的作用尚不明确。通过本课题的研究，我们发现：①RDN可以改善心梗大鼠心功能，降低恶性室性心律失常诱发率；②RDN可以调节纤维化相关的TGF-β1信号通路、降低纤维化相关因子α-SMA、PINP、PIIINP等的表达，延缓心肌纤维化进程，进而降低心律失常诱发率；③RDN可以改善梗死周边区缝隙连接蛋白重构及交感神经过度再生，降低心律失常诱发率；④RDN可以调节心脑氧化应激，这可能是其延缓心肌纤维化并降低心律失常的潜在机制；⑤在临床研究中，RDN可以改善心衰患者心功能，并降低室性电风暴发生。综上，通过本课题的研究，我们证实了RDN在基础及临床中对室性心律失常的预防及治疗效果，并从心肌纤维化的角度阐明了RDN改善心律失常的潜在机制，从而为心律失常的防治提供了有效的治疗策略。