Abstract 4343474: Inhibition of Satellite Glial Cell Activation in Stellate Ganglia Prevents Ventricular Arrhythmogenesis and Remodeling Following Myocardial Infarction

Abstract

Background: Hyperactivity of sympathetic neurons in the stellate ganglia (SG) contributes to ventricular arrhythmias (VAs) and remodeling post-myocardial 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, 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 employed 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 condition. Of note, 2h-MI provoked SG-SGC activation that positively correlated to cardiac sympathetic neurotransmitter (norepinephrine) release. Accordingly, SGC activation in the SG enhanced cardiac sympathetic hyperactivity 2h post-MI while SG-SGC inhibition suppressed MI-induced cardiac sympathetic hyperexcitability. Moreover, the persistent inhibition of SG-SGCs improved ventricular arrhythmogenesis, remodeling and dysfunction, alleviated SG and ventricular sympathetic nerve sprouting 7d post-MI. In addition, the bulk RNA sequencing with SG and pharmacological purinergic receptor P2Y1 (P2Y1R) blockage indicated that P2Y1R/insulin like growth factor binding protein 2 (IGFBP2) signaling might mediate the effects of SG-SGC activation on cardiac sympathetic hyperexcitability post-MI. Conclusions: SGC inhibition in SG rectifies cardiac sympathetic hyperactivity, stabilizes ventricular electrophysiological properties and alleviates cardiac structural and neural remodeling post-MI, and resultantly preventing VAs and cardiac dysfunction. Neuromodulation targeting SG-SGCs exhibits a safe and fruitful strategy for the treatment of MI.