Elevated sympathetic tone exacerbates myocardial ischemia reperfusion injury through enhancing endothelial cell inflammation and apoptosis in chronic pain mice.

Although extensive evidence links chronic pain (CP) to an increased cardiovascular risk, its direct impact on myocardial ischemia-reperfusion (MI/R) remains poorly understood. In mice, CP was induced using chronic constriction injury (CCI) of the brachial plexus. We found that CP significantly increased myocardial infarction area, endothelial cell apoptosis, and inflammation, accompanied by the increase in sympathetic nerve tone around the endothelial cells. Viral tracer results demonstrated the existence of anatomical connections between the superior cervical ganglion (SCG) and the heart. The results of c-Fos staining and heart rate variability monitoring indicated that the SCG-cardiac circuit was excessively activated. Chemical sympathectomy of SCG using 6-hydroxydopamine (6-OHDA) effectively alleviated myocardial injury, endothelial cell apoptosis, and inflammation. Additionally, the NLRP3 inflammasome of endothelial cells was up-regulated in mice with CP. Both ablation of SCG and MCC950 inhibited NLRP3 expression and alleviated myocardial infarction area, endothelial cell apoptosis, and inflammation. Finally, bisoprolol not only reduced heart rate, but also decreased myocardial infarction, inhibited endothelial cell apoptosis, and NLRP3 expression. In conclusion, sympathetic nerve-driven endothelial apoptosis and inflammation were key pathological processes through which CP exacerbated MI/R injury. The sympathetic-NLRP3 pathway contributed at least in part to the phenotype, with endothelial cells as an important but not exclusive target. Although the current data were obtained exclusively from young male mice, these findings establish a conserved mechanistic framework that warrants validation in female, aged, and clinically relevant models.