mGluR1/5在心肌梗死后交感神经重构致心室颤动发生和维持中的作用及分子机制

Ventricular fibrillation (VF) is one of the most common arrhythmias for sudden cardiac death after myocardial infarction (MI). Sympathetic nerve remodeling (SNR) after MI has been shown to be responsible for the lethal arrhythmias such as VF. However, no exact mechanisms, especially molecular mechanisms have yet explained how VF is triggered and maintained by SNR. Recent studies have demonstrated that there were relationships between sympathetic nerve (SN) and glutamate and its receptors. Based on the mechanisms of occurrence of VF after MI and the relationships between SN and glutamate and its receptors, we hypothesize that group I metabotropic glutamate receptors (mGluRs) including mGluR1 and mGluR5 (mGluR1/5) is one of the molecular mechanisms that lead to the occurrence and maintenance of VF induced by SNR after MI. MI and post-MI VF models of dogs will be established and modern molecular biology and electrophysiological techniques will be used in the present project to study the specific mechanisms of mGluR1/5 leading to the occurrence and maintenance of VF, including the signal transduction pathways that regulate the membrane proteins and related ion channels. Meanwhile, the technique of RNA interference will be used to verify the preventive role of the gene silence of mGluR1/5 for VF. These findings will contribute to the understanding of the biological functions of mGluR1/5 and reveal the elements of trigger and matrix for VF after MI, so as to provide new theoretical basis and strategies for the better prevention and treatment of VF after MI.

心室颤动(室颤)是心肌梗死后心脏性猝死最常见的心律失常之一。研究表明，心肌梗死后交感神经重构是室颤发生和维持的重要原因，但其具体分子机制仍不明确。最近的研究表明，交感神经和谷氨酸及其受体有一定的相关性。本项目综合国内外的研究现状，在深入分析心肌梗死后室颤发生机制、交感神经与谷氨酸及其受体关系的基础上，提出了Ⅰ型代谢型谷氨酸受体（mGluR1/5)是心肌梗死后交感神经重构致室颤发生和维持的分子基础的假说。拟通过建立犬心肌梗死和心肌梗死后室颤模型，利用分子生物学及现代电生理学技术，研究mGluR1/5通过其信号转导通路调控膜蛋白及相关离子通道促进室颤发生和维持的机制；并利用RNA干扰技术，探讨特异性沉默mGluR1/5预防室颤发生的可能性。这些研究结果将促进对mGluR1/5生物学功能的认识，有助于进一步揭示心肌梗死后室颤发生和维持的触发与基质因素，从而为更好地防治室颤提供新的理论依据和策略。

项目背景：心室颤动(室颤)是心肌梗死后心脏性猝死最常见的心律失常之一。研究表明，心肌梗死后交感神经重构是室颤发生和维持的重要原因，但其具体分子机制仍不明确。最近的研究表明，交感神经和谷氨酸及其受体有一定的相关性。本项目综合国内外的研究现状，在深入分析心肌梗死后室颤发生机制、交感神经与谷氨酸及其受体关系的基础上，提出了Ⅰ型代谢型谷氨酸受体（mGluR1/5）是心肌梗死后交感神经重构致室颤发生和维持的分子基础的假说。研究内容：通过建立犬心肌梗死和心肌梗死后室颤模型，利用分子生物学及现代电生理学技术，研究mGluR1/5通过其信号转导通路调控膜蛋白及相关离子通道促进室颤发生和维持的机制；并利用RNA干扰技术，探讨特异性沉默mGluR1/5预防室颤发生的可能性。重要结果：心肌梗死后交感神经区域性的分布差异使mGluR1/5在不同部位的激活程度不同；mGluR1/5及其相关分子是心肌梗死后交感神经重构致室颤发生和维持的分子及电生理学基础；利用mGluR1/5特异性siRNA，可以特异性干扰mGluR1/5介导的信号通路导致室颤发生和维持的途径。关键数据：激动剂DHPG主要通过mGluR1而非mGluR5磷酸化Cx43和抑制GJIC；mGluR1的激活主要通过ERK1/2通路而非PKC通路促使Cx43磷酸化和抑制GJIC；mGluR1可以引起细胞内肌浆网Ca2+释放增加；mGluR1引起的肌浆网Ca2+释放增加使心脏组织更易发生室颤。科学意义：这些研究结果将促进对mGluR1/5生物学功能的认识，有助于进一步揭示心肌梗死后室颤发生和维持的触发与基质因素，从而为更好地防治室颤提供新的理论依据和策略。