Alteration of Cholinergic Anti-Inflammatory Pathway in Rat With Ischemic Cardiomyopathy-Modified Electrophysiological Function of Heart.
Alteration of Cholinergic Anti-Inflammatory Pathway in Rat With Ischemic Cardiomyopathy-Modified Electrophysiological Function of Heart.
复制标题
缺血性心肌病大鼠胆碱能抗炎通路的改变-心脏电生理功能的改变
DOI：
10.1161/jaha.117.006510
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发表时间：
2017-09-19
影响因子：
5.4
通讯作者：
Lin JF
中科院分区：
文献类型：
--
作者：
Wu SJ;Li YC;Shi ZW;Lin ZH;Rao ZH;Tai SC;Chu MP;Li L;Lin JF
在心肌梗死后出现慢性缺血时，所形成的瘢痕组织会导致电重构和结构重构，从而容易形成致心律失常的基质。迷走神经通过α7烟碱型乙酰胆碱受体（α7 - nAChR）引发的胆碱能抗炎通路能够调节局部和全身的炎症反应。在此，我们旨在阐明迷走神经在缺血性心肌病（ICM）期间抗心律失常特性的一种新机制。
将成年雄性Sprague - Dawley大鼠的左冠状动脉前降支结扎4周以诱导ICM。蛋白质印迹法显示，通过尼古丁治疗激活胆碱能抗炎通路，可通过抑制NF - κB的活化，使左心室梗死边缘区的胶原蛋白、细胞因子及其他炎症介质的量显著减少，同时使磷酸化连接蛋白43增加。迷走神经切断术抑制了尼古丁给药的抗炎、抗纤维化和抗心律失常作用。免疫组织化学证实，尼古丁给药诱导的连接蛋白43增加位于细胞间连接处。此外，尼古丁处理抑制了脂多糖刺激的RAW264.7细胞中NF - κB的活化，并且α - 银环蛇毒素（一种α7 - nAChR选择性拮抗剂）部分抑制了尼古丁处理的效果。另外，给予尼古丁4周可略微改善心脏功能，增加心脏副交感神经张力，缩短延长的QTc间期，并降低程序性电刺激诱导的室性心律失常的心律失常评分。
激活胆碱能抗炎通路对ICM诱导的室性心律失常具有抗心律失常作用，同时伴有细胞因子下调、胶原蛋白生成减少、交感/副交感比率降低以及在ICM期间防止磷酸化连接蛋白43的丢失。我们的研究结果可能提示，通过激活胆碱能抗炎通路来治疗ICM诱导的室性心律失常是一种有前景的疗法。
With chronic ischemia after myocardial infarction, the resulting scar tissue result in electrical and structural remodeling vulnerable to an arrhythmogenic substrate. The cholinergic anti‐inflammatory pathway elicited by vagal nerve via α7 nicotinic acetylcholine receptors (α7‐nAChR) can modulate local and systemic inflammatory responses. Here, we aimed to clarify a novel mechanism for the antiarrhythmogenic properties of vagal nerve during the ischemic cardiomyopathy (ICM). Left anterior descending artery of adult male Sprague‐Dawley rats was ligated for 4 weeks to develop ICM. Western blot revealed that eliciting the cholinergic anti‐inflammatory pathway by nicotine treatment showed a significant reduction in the amounts of collagens, cytokines, and other inflammatory mediators in the left ventricular infarcted border zone via inhibited NF‐κB activation, whereas it increased the phosphorylated connexin 43. Vagotomy inhibited the anti‐inflammatory, anti‐fibrosis, and anti‐arrhythmogenic effect of nicotine administration. And immunohistochemistry confirmed that the nicotine administration‐induced increase of connexin 43 was located in intercellular junctions. Furthermore nicotine treatment suppressed NF‐κB activation in lipopolysaccharide‐stimulated RAW264.7 cells, and α‐bungarotoxin (an α7‐nAChR selective antagonist) partly inhibited the nicotine‐treatment effect. In addition, 4‐week nicotine administration slightly improved the cardiac function, increased cardiac parasympathetic tone, decreased the prolonged QTc, and decreased the arrhythmia score of programmed electric stimulation‐induced ventricular arrhythmia. Eliciting the cholinergic anti‐inflammatory pathway exerts anti‐arrhythmogenic effects against ICM‐induced ventricular arrhythmia accompanied by downregulation of cytokines, downgenerating of collagens, decrease in sympathetic/parasympathetic ratio, and prevention of the loss of phosphorylated connexin 43 during ICM. Our findings may suggest a promising therapy for the generation of ICM‐induced ventricular arrhythmia by eliciting the cholinergic anti‐inflammatory pathway.