巨噬细胞介导儿茶酚胺反向调控心肌梗死后交感神经重构的研究

Sympathetic nerve remodeling plays an important role in ventricular arrhythmia and sudden death after myocardial infarction (MI). Nerve growth factor (NGF) expressed by local infiltrating macrophage is the key of cardiac sympathetic nerve remodeling, but the regulative mechanism has not been fully researched. Many studies have showed that cardiac sympathetic nerve proliferation is associated with catecholamine and macrophage has adrenergic receptors. The applicant’s previous research demonstrated that myocardial ischemia could induce elevation of local catecholamine concentration. Recently, we performed preliminary experiment on macrophage, which indicated epinephrine promoted NGF expression of macrophage. Therefore, we propose the hypothesis that catecholamine might retrogradely regulate cardiac sympathetic nerve remodeling after MI mediated by macrophage. In other words, catecholamine not only acts on cardiomyocytes as sympathetic transmitter, but also regulates NGF expression of macrophage, and then induces retrograde signals to regulate sympathetic nerve remodeling. We have designed experiments on cellular, tissular and whole-animal levels to test this hypothesis. Through these experiments, the following information would be confirmed: (1) the effect and mechanism of catecholamine inducing NGF expressed by macrophage, (2) the effect of catecholamine inducing NGF expression of macrophage after MI, and regulating sympathetic nerve growth of superior cervical ganglion, (3) the regulative effect of catecholamine mediated by macrophage on sympathetic nerve remodeling and prognosis after MI. Our study will demonstrate the effect and mechanism that sympathetic nerve remodeling after MI is regulated by catecholamine. This will develop a new theory for prevention and treatment of ventricular arrhythmia and sudden death after MI.

心肌梗死后交感神经重构在室性心律失常和猝死发生中起重要作用，局部巨噬细胞浸润表达神经生长因子（NGF）是交感神经重构的关键，但调控机制尚未阐明。研究表明交感神经增生与儿茶酚胺密切相关。申请人的前期研究提示心肌缺血后局部儿茶酚胺水平增加，预实验表明肾上腺素促进巨噬细胞NGF表达。因此我们提出“巨噬细胞介导儿茶酚胺反向调控心肌梗死后交感神经重构”的假说，即交感神经递质儿茶酚胺不仅作用于心肌细胞，而且刺激巨噬细胞合成NGF，形成反向信号调控交感神经重构。本项目拟从细胞、组织和整体动物三个水平设计实验，分别阐明：①儿茶酚胺刺激巨噬细胞合成NGF及机制；②心肌梗死后儿茶酚胺刺激巨噬细胞NGF表达，调控交感神经生长；③儿茶酚胺通过巨噬细胞及NGF调控心肌梗死后交感神经重构并影响预后。本研究将揭示心肌梗死后交感神经重构受儿茶酚胺调控的作用及机制，为心肌梗死后室性心律失常及猝死的防治增添新的理论和依据。

心肌梗死后巨噬细胞浸润表达神经生长因子（NGF）是交感神经重构的关键，而交感神经重构又促进室性心律失常和猝死的发生。已有研究表明儿茶酚胺能够引起巨噬细胞炎症因子表达增加。在此背景之下，本项目主要论证心肌梗死后局部浓度升高的儿茶酚胺能够作用于巨噬细胞表达NGF、从而反向调控交感神经重构、促进室性心律失常发生的假说。项目主要从细胞水平证实儿茶酚胺刺激巨噬细胞合成NGF并探讨其机制、从组织水平明确心肌梗死后儿茶酚胺通过巨噬细胞表达NGF调控交感神经生长、从整体动物水平证实儿茶酚胺调控心肌梗死后交感神经重构并影响预后。研究结果显示，以肾上腺素为代表的儿茶酚胺促进LPS激活的巨噬细胞合成NGF，发现其机制可能通过Notch信号通路参与。心肌梗死后梗死周边区心肌组织巨噬细胞浸润和交感神经增生增加、超声心动图显示左室收缩功能下降、电生理检查显示室颤诱发率明显增加，而β受体阻滞剂能够减缓以上改变，揭示了儿茶酚胺调控心肌梗死后交感神经重构并影响预后。该机制的阐明为心肌梗死后交感神经重构、室性心律失常及猝死的防治寻找到可能的干预靶点并增添了新的理论依据。项目培养硕士研究生1名、国外访问学者和硕士研究生导师1名。SCIE收录杂志接受论著2篇，北大核心期刊杂志发表论文3篇，申请发明专利1项，且预计后期将有另外2篇论著发表于SCIE收录杂志。