Circulation. Arrhythmia and electrophysiology · 2025
Inhibition of Satellite Glial Cell Activation in Stellate Ganglia Prevents Ventricular Arrhythmogenesis and Remodeling After Myocardial Infarction.
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Zhou Zhen, Zhang Hanyu, Xiong Hongbo, Deng Ke-Qiong, Zheng Meng, Zhang Yongkang, Xu Zhendong, Tian Ruifeng, Zhang Tong, Kong Xiangjie, Hu Yingying, Luo Yinhua, Cai Huanhuan, Fan Di, Wang Qing K, He Bo, Wang Qiongxin, Lu Zhibing
Аннотация
BACKGROUND: Hyperactivity of sympathetic neurons in the stellate ganglia (SG) contributes to ventricular arrhythmias and remodeling postmyocardial infarction (MI). However, the role of satellite glial cells (SGCs) surrounding the neurons in this process remains unknown.
METHODS: SGC-specific chemogenetic manipulation was locally applied to modulate SG-SGC activity dual-directionally in the rats with naïve or infarcted hearts. Subsequently, cardiac sympathetic neural activity and ventricular electrophysiological stability in response to stimulation were evaluated, as well as cardiac neural and structural remodeling post-MI. SG bulk RNA sequencing and the interaction between SGCs and sympathetic neurons isolated from SG were used to explore the underpinning mechanisms.
RESULTS: SG-SGC excitation increased SG neural activity and ventricular electrophysiological instability in rats with naïve hearts, whereas its inhibition influenced none of the above under physiological conditions. Of note, 2-hour-MI provoked SG-SGC activation that positively correlated with cardiac sympathetic neurotransmitter (norepinephrine) release. Accordingly, SGC activation in the SG enhanced cardiac sympathetic hyperactivity 2 hours post-MI, whereas SG-SGC inhibition suppressed MI-induced cardiac sympathetic hyperexcitability. Moreover, the persistent inhibition of SG-SGCs improved ventricular remodeling and dysfunction, alleviated SG and ventricular sympathetic nerve sprouting 7 days post-MI. In addition, the bulk RNA sequencing with SG and pharmacological purinergic P2Y1R (P2Y1 receptor) blockage indicated that P2Y1R/IGFBP2 (insulin-like growth factor-binding protein 2) signaling mediated the effects of SG-SGC activation on cardiac sympathetic hyperexcitability post-MI, and IGFBP2 bridged the interaction between the neurons and surrounding SGCs.
CONCLUSIONS: SGC inhibition in SG rectifies cardiac sympathetic hyperactivity, stabilizes ventricular electrophysiological properties, and alleviates cardiac structural and neural remodeling post-MI, thereby preventing ventricular arrhythmias and cardiac dysfunction. Neuromodulation targeting SG-SGCs exhibits a safe and fruitful strategy for the treatment of MI.
METHODS: SGC-specific chemogenetic manipulation was locally applied to modulate SG-SGC activity dual-directionally in the rats with naïve or infarcted hearts. Subsequently, cardiac sympathetic neural activity and ventricular electrophysiological stability in response to stimulation were evaluated, as well as cardiac neural and structural remodeling post-MI. SG bulk RNA sequencing and the interaction between SGCs and sympathetic neurons isolated from SG were used to explore the underpinning mechanisms.
RESULTS: SG-SGC excitation increased SG neural activity and ventricular electrophysiological instability in rats with naïve hearts, whereas its inhibition influenced none of the above under physiological conditions. Of note, 2-hour-MI provoked SG-SGC activation that positively correlated with cardiac sympathetic neurotransmitter (norepinephrine) release. Accordingly, SGC activation in the SG enhanced cardiac sympathetic hyperactivity 2 hours post-MI, whereas SG-SGC inhibition suppressed MI-induced cardiac sympathetic hyperexcitability. Moreover, the persistent inhibition of SG-SGCs improved ventricular remodeling and dysfunction, alleviated SG and ventricular sympathetic nerve sprouting 7 days post-MI. In addition, the bulk RNA sequencing with SG and pharmacological purinergic P2Y1R (P2Y1 receptor) blockage indicated that P2Y1R/IGFBP2 (insulin-like growth factor-binding protein 2) signaling mediated the effects of SG-SGC activation on cardiac sympathetic hyperexcitability post-MI, and IGFBP2 bridged the interaction between the neurons and surrounding SGCs.
CONCLUSIONS: SGC inhibition in SG rectifies cardiac sympathetic hyperactivity, stabilizes ventricular electrophysiological properties, and alleviates cardiac structural and neural remodeling post-MI, thereby preventing ventricular arrhythmias and cardiac dysfunction. Neuromodulation targeting SG-SGCs exhibits a safe and fruitful strategy for the treatment of MI.