International immunopharmacology · 2026
Apelin-13 alleviates post-infarction injury by modulating macrophage inflammation via APJ-dependent inhibition of NLRP3-mediated pyroptosis.
СтатьяНазвание и аннотация: Перевод в очереди
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Xu Xian-Jie, Shen Kuo, Ma Yu-Jie, Zhang Xiao-Li, Wang Qi, Liu Peng, He Qi-Fen, Wang Xian-Qi, Xu Ya-Nan, Fu He-Liang, Yang Ke-Xun, Li Jun-Jie, Luo Zheng-Xue
Аннотация
BACKGROUND: Sustained macrophage-driven inflammation critically exacerbates post-infarction myocardial injury and remodeling. While Apelin-13 (A13) is known for its cardiovascular benefits, its direct immunomodulatory role on macrophages after myocardial infarction (MI) remains undefined.
METHODS: We established a mouse MI model and a hypoxia/hypoglycemia (Hyp) model with macrophage-cardiomyocyte Transwell co-culture. A13 was administered systemically in vivo and used for macrophage preconditioning in vitro. For functional validation, A13-modulated macrophages were transplanted intramyocardially into infarcted hearts. Comprehensive molecular profiling encompassed RNA sequencing, western blotting, flow cytometry, and cytokine ELISA. Specific inhibitors were applied to dissect the APJ/NLRP3 axis.
RESULTS: A13 treatment significantly improved cardiac function, attenuated adverse remodeling, and suppressed pro-inflammatory cytokine release. Importantly, intramyocardial transplantation of A13-modulated macrophages directly mitigated the injury-aggravating effects of stressed macrophages, as evidenced by improved cardiac function, reduced fibrosis and inflammatory infiltration, and attenuated oxidative damage. Transcriptomic analysis identified reversal of Hyp-induced pro-inflammatory signatures, with marked enrichment in the NOD-like receptor pathway. A13 acted through the APJ receptor to inhibit NLRP3 inflammasome assembly, Caspase-1 activation, GSDMD cleavage, and IL-1β maturation, thereby suppressing macrophage pyroptosis.
CONCLUSIONS: Our findings uncover a novel mechanism by which A13 alleviates post-MI injury through APJ-dependent inhibition of NLRP3-mediated pyroptosis in macrophages, providing a promising immunomodulatory axis for therapeutic intervention.
METHODS: We established a mouse MI model and a hypoxia/hypoglycemia (Hyp) model with macrophage-cardiomyocyte Transwell co-culture. A13 was administered systemically in vivo and used for macrophage preconditioning in vitro. For functional validation, A13-modulated macrophages were transplanted intramyocardially into infarcted hearts. Comprehensive molecular profiling encompassed RNA sequencing, western blotting, flow cytometry, and cytokine ELISA. Specific inhibitors were applied to dissect the APJ/NLRP3 axis.
RESULTS: A13 treatment significantly improved cardiac function, attenuated adverse remodeling, and suppressed pro-inflammatory cytokine release. Importantly, intramyocardial transplantation of A13-modulated macrophages directly mitigated the injury-aggravating effects of stressed macrophages, as evidenced by improved cardiac function, reduced fibrosis and inflammatory infiltration, and attenuated oxidative damage. Transcriptomic analysis identified reversal of Hyp-induced pro-inflammatory signatures, with marked enrichment in the NOD-like receptor pathway. A13 acted through the APJ receptor to inhibit NLRP3 inflammasome assembly, Caspase-1 activation, GSDMD cleavage, and IL-1β maturation, thereby suppressing macrophage pyroptosis.
CONCLUSIONS: Our findings uncover a novel mechanism by which A13 alleviates post-MI injury through APJ-dependent inhibition of NLRP3-mediated pyroptosis in macrophages, providing a promising immunomodulatory axis for therapeutic intervention.