Interaction between Endothelin-1 and Left Stellate Ganglion Activation: A Potential Mechanism of Malignant Ventricular Arrhythmia during Myocardial Ischemia.

Zhenya Wang,Shuyan Li,Liping Zhou,Menglong Wang,Yanqiu Lai,Xiaoya Zhou,Hui Chen,Hong Jiang,Guannan Meng,Zhuo Wang,Huanzhu Lai

doi:10.1155/2019/6508328

Abstract

Endothelin-1 (ET-1) is synthesized primarily by endothelial cells. ET-1 administration in vivo enhances the cardiac sympathetic afferent reflex and sympathetic activity. Previous studies have shown that sympathetic hyperactivity promotes malignant ventricular arrhythmia (VA). The aim of this study was to investigate whether ET-1 could activate the left stellate ganglion (LSG) and promote malignant VA. Twelve male beagle dogs who received local microinjections of saline (control, n = 6) and ET-1 into the LSG (n = 6) were included. The ventricular effective refractory period (ERP), LSG function, and LSG activity were measured at different time points. VA was continuously recorded for 1 h after left anterior descending occlusion (LADO), and LSG tissues were then collected for molecular detection. Compared to that of the control group, local ET-1 microinjection significantly decreased the ERP and increased the occurrence of VA. In addition, local microinjection of ET-1 increased the function and activity of the LSG in the normal and ischemic hearts. The expression levels of proinflammatory cytokines and the protein expression of c-fos and nerve growth factor (NGF) in the LSG were also increased. More importantly, endothelin A receptor (ETA-R) expression was found in the LSG, and its signaling was significantly activated in the ET-1 group. LSG activation induced by local ET-1 microinjection aggravates LADO-induced VA. Activated ETA-R signaling and the upregulation of proinflammatory cytokines in the LSG may be responsible for these effects.

Highlights

Malignant ventricular arrhythmia (VA) is a main cause of sudden cardiac death after acute myocardial infarction
There were no significant differences in left stellate ganglion (LSG) function before or after local microinjection (Figure 2(b))
(Figure 7(b)), and the results indicated that compared to the control treatment, ET-1 microlocal microinjection significantly decreased the activation of phosphoinositide 3-kinase (PI3K) and Akt and stimulated the phosphorylation of glycogen synthase kinase- (GSK-)3β in the LSG, which induced the activation of the PI3K/Akt/GSK-3β pathway via ET-1 binding to the endothelin A receptor (ETA-R) as a potential mechanism for LSG hyperactivity

Summary

Introduction

Malignant ventricular arrhythmia (VA) is a main cause of sudden cardiac death after acute myocardial infarction. A recent clinical study demonstrated that stellate ganglion dysfunction results in excessive and dysfunctional efferent sympathetic tone in patients with cardiomyopathy and refractory VA [4]. These findings indicate that LSG hyperactivity may be a major trigger for malignant VA. Clinical studies have shown that the plasma levels of endothelin-1 (ET-1) are markedly increased in patients with sympathetic hyperactivity cardiovascular disease, such as patients with myocardial infarction [5] and hypertension [6], which suggests that ET-1 may play a key role in the regulation of sympathetic activity

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Conclusion