Nerve Sprouting Contributes to Increased Severity of Ventricular Tachyarrhythmias by Upregulating iGluRs in Rats with Healed Myocardial Necrotic Injury
Nerve Sprouting Contributes to Increased Severity of Ventricular Tachyarrhythmias by Upregulating iGluRs in Rats with Healed Myocardial Necrotic Injury
复制标题
神经萌芽通过上调心肌坏死损伤大鼠的 iGluRs 导致室性快速心律失常的严重程度增加
DOI：
10.1007/s12031-012-9720-x
复制
发表时间：
2012-10-01
影响因子：
3.1
通讯作者：
Cao, Ji-Min
中科院分区：
文献类型：
--
作者：
Lu, Jing;Gao, Xue;Cao, Ji-Min
心肌梗死（MI）愈合后交感神经出芽与致死性心律失常的高发生率有关，但其潜在机制尚不清楚。本研究旨在测试交感神经过度支配和/或MI重塑心肌谷氨酸信号传导并最终增加室性快速性心律失常的严重程度。心肌坏死性损伤（MNI）是通过液氮冻融横跨完整的隔膜来模拟MI。慢性皮下注射4-甲基儿茶酚，神经生长因子表达的有效刺激剂，引起心脏交感神经过度支配。结果表明，交感神经支配增强或不增强MNI均可上调心肌细胞离子型谷氨酸受体（iGluRs），包括NMDA受体（NMDAR）和AMPA受体（AMPAR）的表达，并诱导心肌细胞凋亡。静脉输注NMDA（12 mg/kg）或AMPA（15 mg/kg）引发室性心动过速和室颤大鼠愈合的MNI加上交感神经支配亢进，这些心律失常的NMDAR或AMPAR的拮抗剂防止。我们的结论是，MNI与交感神经发芽上调NMDAR和AMPAR在心肌中的表达，这种影响反过来又增强心脏对iGluRs刺激的反应，从而增加室性快速性心律失常的发病率。
Sympathetic nerve sprouting in healed myocardial infarction (MI) has been associated with high incidences of lethal arrhythmias, but the underlying mechanisms are largely unknown. This study sought to test that sympathetic hyperinnervation and/or MI remodels the myocardial glutamate signaling and ultimately increases the severity of ventricular tachyarrhythmias. Myocardial necrotic injury (MNI) was created by liquid nitrogen freeze–thawing across an intact diaphragm to mimic MI. Cardiac sympathetic hyperinnervation was induced by chronic subcutaneous injection of 4-methylcatechol, a potent stimulator of nerve growth factor expression. The results showed that sympathetic hyperinnervation with or without MNI upregulated the myocardial expression of ionotropic glutamate receptors (iGluRs), including NMDA receptor (NMDAR) and AMPA receptor (AMPAR), and induced cardiomyocyte apoptosis. Intravenous infusion with either NMDA (12 mg/kg) or AMPA (15 mg/kg) triggered ventricular tachycardia and ventricular fibrillation in rats with healed MNI plus sympathetic hyperinnervation; these arrhythmias were prevented by respective antagonist of NMDAR or AMPAR. We conclude that MNI with sympathetic nerve sprouting upregulates the expression of NMDAR and AMPAR in the myocardium and this impact in turn enhances cardiac responses to stimulations of iGluRs and thus increases the incidence of ventricular tachyarrhythmias.