Type-2 Diabetes Mellitus (T2DM) is related to cardiac arrhythmias. The stellate ganglion (SG), part of the sympathetic nervous system, regulates heart function. Within the SG, satellite glial cells (SGCs) have gap junction channels (Cx43). Increased Cx43 permeability induces SGC depolarization and activates the PKC-MAPK14-ADAM17 signaling pathway, releasing some endogenous factors that stimulate nearby cardiac postganglionic sympathetic neurons (CPSN). This study investigated the activation of the PKC-MAPK14-ADAM17 signaling pathway in T2DM SGs and SGCs as a novel mechanism of sympathetic overactivation. A total of 56 Sprague-Dawley rats were randomly assigned to sham and T2DM groups, and T2DM was induced using a high-fat diet combined with low-dose streptozotocin. Real-time RT-PCR, Western blot, and ELISA quantified mRNA/protein expression and enzymatic activity. The patch clamp technique assessed neuronal voltage-gated Ca²⁺ currents and action potentials, while electrophysiological recording measured cardiac sympathetic nerve activity (CSNA). T2DM rats exhibited marked upregulation of MAPK14, PKC-α, and ADAM17 mRNA/protein in the SG, alongside elevated enzymatic activities of PKC and ADAM17. T2DM also increased Ca²⁺ currents and neuronal excitability in the CPSN and induced the elevation of the CSNA. Upregulated PKC-MAPK-ADAM17 signaling in the SG might contribute to cardiac sympathetic overactivation in T2DM rats by enhancing the cell excitability of the CPSN.

Chronic heart failure (CHF) is characterized by heightened cardiac sympathetic activity and neuroinflammation within the stellate ganglia (SG), contributing to cardiac arrhythmogenesis. However, the upstream mediators of this neuroimmune interaction remain incompletely defined. This study investigated whether systemic neutralization of granulocyte–macrophage colony-stimulating factor (GM-CSF, an inflammatory cytokine) attenuates SG inflammation and cardiac sympathetic overactivation in a rat model of coronary artery ligation-induced CHF. Male Sprague–Dawley rats underwent myocardial infarction or sham surgery and were treated with a GM-CSF neutralizing antibody or vehicle. Cardiac sympathetic nerve activity (CSNA), heart rate variability (HRV), cytokine expression, and the electrophysiological properties of cardiac sympathetic post-ganglionic (CSP) neurons were assessed. CHF increased the levels of GM-CSF, ionized calcium-binding adaptor molecule 1 (IBA1, an activated macrophage marker) and pro-inflammatory markers (TNF-α, pro IL-1β) in the SG, enhanced neuronal Ca²⁺ currents, cell excitability, and CSNA, and impaired HRV. The GM-CSF neutralizing antibody significantly attenuated SG inflammation, partially normalized Ca²⁺ currents and neuronal firing, decreased CSNA, and improved cardiac autonomic balance. These findings identify GM-CSF as a key regulator of SG neuroinflammation and sympathetic dysregulation in CHF. Targeting this GM-CSF protein may represent a novel therapeutic strategy to mitigate autonomic imbalance and arrhythmic risk.