心肌梗死后氧化应激促心脏交感神经重构的分子机制研究

Malignant ventricular arrhythmia is one of the direct lethal cause in patients with myocardial infarction（IM）. Our previous researches on sympathetic nerve remodeled in myocardial tissue after IM showed that the densities of both growth associated protein-43(GAP-43) and tyrosine hydroxylasee(TH) positive staining nerve fibers were significantly higher, and there were abnormal expression in some cytokines, such as nerve growth factor and interleukin. Resveratrol may improve sympathetic neural remodeling and reduce arrhythmia through anti-oxidative stress and anti-inflammatory responses. These indicated that oxidative stress and inflammatory responses involved in sympathetic neural remodeling, but the mechanisms have not yet been fully elucidated. This project intends to investigate the mechanism of sympathetic neural remodeling induces arrhythmia after MI by following research in a transgenic mice model of reactive oxygen species(mt-cpYFP). Firstly, the effects of MI on ROS releasing and of resvratrol on sympathetic neural remodeling by quenching ROS. Secondly, the mechanism of the key target molecular ROS produced on sympathetic neural remodeling. Thirdly, the mechanism of the key target molecular ROS acting on sympathetic neural remodeling. Lastly, we research on the feasibility of reducing ympathetic neural remodeling and production of arrhythmia by interventing the key target molecular ROS produced and acting. These researches will provide therapy for arrhythmia.

恶性心律失常是心肌梗死（MI）患者的直接死亡原因之一。我们对MI后心肌组织交感神经重构的研究表明：反映神经轴突发生的生长相关蛋白-43阳性神经细胞的密度增加，交感神经标志物酪氨酸羟化酶异常分布，神经生长因子和白介素等异常表达；而白藜芦醇通过抗氧化应激及炎症反应改善交感神经重构使心律失常减少，说明氧化应激和炎症反应参与了交感神经重构，但其机制尚不清楚。本标书拟在活性氧（ROS）在体检查转基因小鼠模型（mt-cpYFP）研究：1）MI对ROS释放的影响和白藜芦醇ROS淬灭影响神经重构的机制；2）ROS产生系统关键分子对神经重构的作用机制；3）ROS作用的关键靶分子在神经重构中的作用机制；4）通过对ROS产生系统关键分子和ROS作用的关键靶分子干预，减少神经重构和心律失常发生的可能性。探讨MI后交感神经重构对心律失常发生的诱发机制，为MI患者抗心律失常治疗打下基础。

研究背景：氧化应激与炎症反应除了加重心肌缺血损伤，还促进心肌梗死后心脏交感神经重构。本课题组在前期研究中发现，天然抗氧化剂白藜芦醇可以抑制炎症反应并有效改善梗死后心脏交感神经重构。然而，氧化应激与炎症反应如何相互作用，以及二者调控心脏交感神经重构的具体机制尚不完全明确。.主要研究方法与结果：1）检测冠心病和急性心肌梗死患者的循环血指标，发现TGF-β1/SMAD3通路与冠心病发生相关，miR-19a与急性心肌梗死发生相关；2）基因多态性分析结果显示，AhR基因的rs2066853位点为中国汉族人群发生冠心病的易感基因；3）应用心肌细胞缺氧模型与动物心肌梗死模型，证实白藜芦醇可以清除多余活性氧、上调抗氧化系统活性，并抑制NF-κB通路介导的炎症反应；4）急性心肌梗死后心肌组织中AhR表达增高，黄芩苷通过抑制AhR基因表达减轻心肌缺血损伤与炎症反应；5）应用心脏成纤维细胞和PC12细胞共培养模型，以及心肌梗死后心脏交感神经重构动物模型，揭示了心肌梗死后心肌组织中高表达的IL-1β是促进心脏成纤维细胞分泌NGF，进而引起交感神经重构的主要炎症因子，白藜芦醇则通过上调抗氧化系统活性和抑制NOX4/ROS/NF-κB信号轴激活，对抗心肌梗死后交感神经重构。`.结论：在急性心肌梗死发生、发展的过程中，氧化应激与炎症反应相互促进，一方面加重心肌损伤，另一方面促进心脏交感神经重构；抗氧化抗炎治疗可以有效改善心肌缺血损伤，并抑制心肌梗死后神经重构。.意义：揭示了心肌梗死后促进心脏交感神经重构的关键分子与信号通路，并阐明了白藜芦醇的作用机制，为防治心肌梗死后室性心律失常奠定了理论基础，并提供新思路。