Neuropilin-1对大鼠心肌梗死后室性心律失常的影响及其机制的实验研究

Malignant ventricular tachyarrhythmia is one of the most frequent causes of sudden cardiac death (SCD) in patients with myocardial ischemia or infarction. Electrical remodeling at infarct border zone has been shown to contribute to the occurrence of ventricular arrhythmias after myocardial infarction (MI). Electrical remodeling is causally associated with sympathetic neural remodeling in MI. Semaphorin 3A (Sema3A), a potent neural chemorepellent for sympathetic axons, has been demonstrated to suppress sympathetic neural remodeling after MI. Neuropilin-1 is a receptor for Sema3A. Our previous study found that Sema3A can ameliorate electrical remodeling at infarct border zones after MI. In this study, we construct of adenoviral vectors carrying neuropilin-1 gene and injected into the infarct border zone. In vitro, neuropilin-1, cell cycle and apoptosis, as well as on ion channels will be detected. In vivo, electrophysiological properties including heart rate variability (HRV), monophasic action potential duration (MAPD) and effective refractory period (ERP) and the expression of arrhythmia-related ion channel proteins at the infarcted border of the left ventricle were examined. The expression of growth associated protein 43 (GAP43) and tyrosinehydroxylase (TH) and the mechanismes at the peri-infarct zones were examined .The present study is to investigate the effectiveness and feasibility of gene therapy in the prevention and treatment of ventricular arrhythmias after MI, which completely break through the limitations of the current anti-arrhythmic drug prevent ventricular arrhythmias after MI.

室性心律失常是引起患者死亡的主要原因，心梗后交感神经重构和电重构是心梗后室性心律失常的发生机制之一。Sema3A 是神经生长发育的过程中最关键的调节因素，neuropilin-1是Sema3A的受体。我们前期的研究发现，Sema3A 显著抑制心梗后室性心律失常发生。本项目拟构建携带neuropilin-1基因的腺病毒载体，在细胞部分实验观察 neuropilin-1在大鼠心肌细胞中的表达，以及对离子通道、细胞周期和凋亡等方面的影响；在动物实验中，将携带 neuropilin-1 基因的腺病毒载体转染大鼠心肌梗死后梗死周边区心肌细胞，观察 neuropilin-1对大鼠心肌梗死后心脏交感神经重构和电重构的影响并探讨其机制，以探讨基因治疗在防治心梗慢性期室性心律失常发生中的有效性和可行性，完全突破目前抗心律失常药物预防心梗后室性心律失常的局限，是对室性心律失常治疗策略的全新探索。