Cardiac-specific sympathetic modulation, not splenic innervation, mediates PC6 electroacupuncture-induced cardioprotection via M2 macrophage polarization in mice with acute myocardial infarction

OBJECTIVE: Electroacupuncture (EA) at Neiguan (PC6) acupoint confers protection against myocardial injury, though its precise neuroimmune mechanisms are not well understood. This study investigates whether EA-mediated attenuation of cardiac inflammation occurs through localized sympathetic and splenic regulation. METHODS: Acute myocardial infarction was induced in mice by coronary artery ligation. Preoperative EA was administered bilaterally at PC6 (2/15 Hz, 1 mA, 20 min/d for 3 d). Cardiac function was assessed by echocardiography. Myocardial inflammation was evaluated by hematoxylin and eosin staining, and infarct size was measured by 2,3,5-triphenyltetrazolium chloride staining. Macrophage recruitment and polarization (toward M2) were analyzed using flow cytometry. Serum norepinephrine, acetylcholine and pro-inflammatory cytokines were measured using enzyme-linked immunosorbent assay, whereas myocardial cytokines were evaluated using immunohistochemistry staining. Splenic sympathetic activity was indexed through tyrosine hydroxylase expression via immunofluorescence staining. The neural pathways were dissected through chemical sympathectomy, splenic denervation, and adoptive splenocyte transfer. RESULTS: EA at PC6 significantly attenuated myocardial inflammation by suppressing cardiac sympathetic activity, downregulating pro-inflammatory cytokines interleukin-6, interleukin-1β and tumor necrosis factor-α, and promoting M2 macrophage polarization. These effects correlated with reduced infarct size, diminished immune cell infiltration, and improved cardiac function. Chemical sympathectomy mimicked EA's cardioprotective profile. Splenic denervation exacerbated systemic inflammation but did not impair EA-driven macrophage phenotypic switching. Adoptive splenocyte transfer, regardless of donor EA pretreatment, facilitated cardiac repair, arguing against a splenocyte-mediated mechanism for EA-induced cardioprotection. CONCLUSION: EA at PC6 exerts its cardioprotective effect primarily through modulating local cardiac sympathetic hyperactivity, which rebalances macrophage polarization toward the M2 phenotype and mitigates inflammation-induced injury. While the spleen contributes to systemic immunity, it plays a minimal role in EA-driven myocardial repair. Please cite this article as: Jiang MJ, Peng R, Lu XH, Yan YH, Qian DY, Zou LY, Liu XE, Chen LY, Bai H, Zhuang Y, M.L. Yu, S.F. Lu. Cardiac-specific sympathetic modulation, not splenic innervation, mediates PC6 electroacupuncture-induced cardioprotection via M2 macrophage polarization in mice with acute myocardial infarction. J Integr Med. 2026; Epub ahead of print.