Sinomenine attenuates post-infarction ventricular remodeling and cardiac dysfunction by suppressing α7nAChR-dependent M1 macrophage polarization and pyroptosis

Purpose To determine whether sinomenine protects against post-infarction ventricular remodeling and cardiac dysfunction by suppressing M1 macrophage polarization and pyroptosis via α7 nicotinic acetylcholine receptor (α7nAChR). Methods A mouse myocardial ischemia-reperfusion (MIRI) model, hypoxia/reoxygenation (H/R)-exposed RAW264.7 macrophages, and primary macrophages were used. At 24 h post-MIRI and post-H/R, pro-inflammatory cytokines (TNF-α, IL-6), M1 markers (CD86, iNOS), M2 markers (CD206, Arg-1), α7nAChR expression, and pyroptotic proteins (NLRP3, cleaved caspase-1, GSDMD-N, mature IL-1β, mature IL-18) were measured. Pyroptotic mRNAs (Nlrp3, Casp1, Gsdmd, Il1b, Il18) were quantified by qRT-PCR. At 28 days post-MIRI, cardiac function (left ventricular ejection fraction, LVEF; left ventricular fractional shortening, LVFS), left ventricular weight, and heart weight were assessed. The selective antagonist methyllycaconitine and specific siRNA were employed to verify α7nAChR involvement. Results In MIRI mice, sinomenine reduced serum and myocardial TNF-α and IL-6, upregulated myocardial α7nAChR, and suppressed CD68+CD86+ and CD68+GSDMD-N+ cardiac macrophages. At 28 days, it improved LVEF and LVFS and reduced left ventricular weight and heart weight. In H/R-exposed RAW264.7 cells, sinomenine decreased TNF-α and IL-6 release, suppressed M1 markers and pyroptotic proteins, restored cell viability, and increased M2 markers and α7nAChR expression. Consistently, sinomenine downregulated pyroptotic mRNAs. These effects were confirmed in primary macrophages. All effects were abolished by α7nAChR inhibition. Conclusion These results suggest that sinomenine alleviates post-infarction ventricular remodeling and cardiac dysfunction by inhibiting M1 polarization and pyroptosis in an α7nAChR-dependent manner. Thus, targeting macrophage α7nAChR may offer a novel immunomodulatory strategy for post-infarction heart failure, with sinomenine as a potential therapeutic candidate.