P2Y6 receptor in the superior cervical ganglion: a key mediator of post-myocardial ischemic sympathetic hyperexcitability via NF-κB mediated neuroinflammation.

Abstract

Myocardial ischemia (MI) often leads to sympathetic overexcitation, though the underlying mechanisms are not fully understood. This work was to elucidate the role of P2Y6 receptors in the superior cervical ganglion (SCG) in mediating sympathetic hyperactivity after MI. In vivo, a rat model of MI was established by mild ligation of the left anterior descending coronary artery. These rats exhibited ST-segment elevation, elevated blood pressure, increased heart rate, enhanced sympathetic nerve discharge, raised serum norepinephrine levels, and structural damage to myocardial tissue. These changes were accompanied by P2Y6 expression upregulation in the SCG and NF-κB signalling activation, as indicated by increased levels of p65, phospho-p65, IL-1β, and TNF-α. P2Y6 knockdown with shRNA significantly alleviated these pathological manifestations. In vitro, oxygen-glucose deprivation in PC12 cells similarly upregulated P2Y6 expression and activated NF-κB signalling. The P2Y6 agonist UDP further enhanced, while the antagonist MRS2578 suppressed, the expression of p65, phospho-p65, IL-1β, and TNF-α. Moreover, the NF-κB inhibitor PTD-P65-P1 abolished UDP-induced IL-1β release. In conclusion, P2Y6 receptors in the SCG contribute to MI-related sympathetic overactivity via NF-κB-mediated inflammatory signalling, highlighting P2Y6 as a potential therapeutic target for autonomic dysregulation after myocardial ischemia.