Superior cervical sympathetic ganglionectomy protects against diabetic myocardial ischemia/reperfusion injury via α7nAChR/JAK2/STAT3 signaling pathway

Background Diabetes mellitus is frequently accompanied by cardiac autonomic neuropathy. Autonomic dysregulation, characterized by a shift toward sympathetic predominance and concomitant vagal withdrawal, prominently exacerbates aseptic inflammation and apoptosis following myocardial ischemia/reperfusion (MI/R) injury. This study elucidates the cardioprotective efficacy of superior cervical sympathetic ganglionectomy (SCGx) against diabetic MI/R injury and characterizes its underlying neuroimmune regulatory mechanisms. Methods A well-established diabetic mouse model characterized by metabolic dysregulation and marked hyperglycemia was established using a high-fat diet combined with streptozotocin (HFD/STZ). SCGx was performed 24 h prior to MI/R injury (30-min ischemia/24-h reperfusion), and multi-dimensional evaluations were conducted via heart rate variability, echocardiography, histopathology, TUNEL staining, and ELISA. The involvement of the α7 nicotinic acetylcholine receptor (α7nAChR) pathway in vivo was interrogated using the specific agonist GTS-21 and the antagonist MLA. Results Our results demonstrate that HFD/STZ-induced diabetic mice subjected to MI/R exhibited marked sympathovagal imbalance and aggravated myocardial injury. SCGx significantly reduced myocardial tyrosine hydroxylase (TH) expression and the low-frequency/high-frequency (LF/HF) ratio, minimized infarct size, and preserved left ventricular systolic function. Concurrently, SCGx lowered serum CK-MB and LDH activities, suppressed infarct-infiltrating Iba1-positive macrophage accumulation, and inhibited pro-inflammatory cytokine release. Furthermore, cardiomyocyte apoptosis was attenuated by downregulating Bax and restoring Bcl-2 levels. Mechanistically, SCGx treatment engaged an α7nAChR-dependent signaling cascade, upregulating α7nAChR expression on infarct-associated macrophages and stimulating myocardial tissue-level JAK2/STAT3 phosphorylation. Pharmacological blockade with MLA substantially blunted these protective benefits, confirming the pivotal contributing role of this signaling axis in the diabetic heart. Conclusion In conclusion, SCGx mitigates diabetic MI/R injury by rebalancing sympathovagal tone and activating the myocardial α7nAChR/JAK2/STAT3 signaling axis. In this neuroimmune protective loop, infarct-associated macrophages act as a key cellular target for α7nAChR engagement to curb inflammation, while tissue-level JAK2/STAT3 activation orchestrates comprehensive cardioprotection against apoptosis.