EphrinB2-NF-κB通路对心肌梗死后心脏交感神重构的影响及调控机制

Cardiac sympathetic neural remodeling after myocardial infarction (MI) is highly associated with a high incidence of ventricular arrhythmias and sudden cardiac death. However, the mechanisms of nerve sprouting and remodeling induced by MI are unclear. Axon guidance molecules EphrinB2 plays critical roles in the differentiation, survival, growth, and synaptic activity of the sympathetic nervous system. Our preliminary experiments showed that EphrinB2 inhibits sympathetic neurite outgrowth in vitro, and the expressions pattern of EphrinB2 is negatively correlated with sympathetic innervations after MI. Furthermore, reported evidences speculated a cross-talk between EphrinB2/EphB2 pathway and NF-κB, and our previous study indicated that cardiac nerve sprouting after MI is associated NF-κB activation, and inhibition of NF-κB activity could ameliorate sympathetic hyperinnervation after MI. All together supposed the hypothesis that EphrinB2 may ameliorate sympathetic hyperinnervation via regulating NF-κB activation. In this study, we plan to use sympathetic neurons culture and rat MI model to examine whether EphrinB2 could regulate NF-κB activation, which participates in the process of cardiac sympathetic sprouting and remodeling after MI. The study will provide new therapeutic targets for cardiac arrhythmias and sudden cardiac death induced by cardiac sympathetic neural remodeling after MI.

心肌梗死（MI）后恶性心律失常的发生与交感神经重构密切相关，但MI后交感神经重构机制尚不明确。轴突导向分子EphrinB2在神经发育和重塑过程发挥重要作用，我们初步研究发现EphrinB2能抑制体外培养交感神经元轴突生长，且MI后心肌EphrinB2动态表达趋势与心脏交感神经再生呈负性相关。有研究提示NF-κB与EphrinB2通路之间存在直接或间接的相互作用，我们既往研究证实NF-κB激活是MI后交感神经再生的关键环节，抑制NF-κB激活可显著改善MI后心脏交感神经重构，上述研究提示EphrinB2有可能通过调控NF-κB的活性参与MI后心脏交感神经重构。本研究拟在交感神经元体外培养、大鼠MI模型基础上，分析EphrinB2通路对MI后心脏交感神经重构的影响，探讨NF-κB介导EphrinB2调控MI后心脏交感神经重构的可能性，以期为MI后因交感经重构导致恶性心律失常的防治提供新思路。

心肌梗死（MI）后恶性心律失常的发生与交感神经重构所致的自主神经失衡密切相关，但MI后交感神经重构机制尚不明确。为明确心肌梗死后交感神经重构及其导致心电不稳定的具体机制，本研究在MI大鼠模型基础上，通过上调或下调EphrinB2表达，以及PVN靶向干预，探讨MI后调控心肌EphrinB2表达及干预中枢系统室旁核（PVN）内NF-κB通路对心肌梗死后交感神经再生的影响及其可能机制。我们的研究发现：（1）心脏梗死后NGF和EphrinB2表达失衡导致交感神经过度再生。通过上调EphrinB2表达，可改善MI后交感神经过度再生及重构，从而进一步降低MI后恶性心律失常的发生率。而这一过程可能是通过激活RhoA介导的神经轴索回缩实现的。（2）靶向调控PVN中NF-κB信号通路可通过下调IL-1β及NGF蛋白表达水平来改善MI后的交感神经再生。这一结果提示靶向调控PVN中的NF-κB可成为改善MI后心脏交感神经重构及降低心律失常发生率的新的靶点。上述结果显示心肌梗死后心脏自主神经失衡是多因素共同作用的结果，调节EphrinB2-RhoA表达可作为有效靶点平衡心脏自主神经支配，增加心电稳定性，降低对室性心律失常的易感性。同时，本研究初步阐述PVN是连接中枢神经和心脏交感神经的桥梁，靶向调控PVN中NF-κB信号通路可抑制MI后心脏交感神经过度再生及重构，为今后进一步深入研究心肌梗死后自主神经失衡的分子信号机制提供新的研究方向。