FASEB J. 2026 Mar 31;40(6):e71635. doi: 10.1096/fj.202501845RRR.
ABSTRACT
Myocardial infarction (MI) remains a leading cause of heart failure and mortality worldwide despite advances in reperfusion strategies and pharmacological therapies. Post-infarction inflammation, particularly macrophage-driven immune responses, plays a critical role in myocardial injury and repair. Vericiguat (VIT), a soluble guanylate cyclase (sGC) stimulator approved for chronic heart failure, has been shown to exert cardioprotective effects; however, its immunomodulatory mechanisms remain incompletely understood. In this study, we demonstrate that vericiguat significantly attenuates myocardial injury and inflammatory responses following MI, accompanied by a shift in macrophage polarization toward an anti-inflammatory phenotype. Integrated transcriptomic and proteomic analyses identified Birc5 (Survivin) as a differentially regulated molecule potentially linked to these effects. In vivo myocardial tissue analyses and confocal immunofluorescence revealed altered spatial associations between Survivin expression and macrophage phenotypes after MI, which were partially restored by vericiguat treatment. Furthermore, in vitro Survivin knockdown attenuated the ability of vericiguat to modulate macrophage polarization and inflammatory signaling. Collectively, these findings indicate that vericiguat-mediated cardioprotection is associated with immunomodulatory effects involving the Survivin/Caspase-6 pathway, providing new insights into the pleiotropic actions of sGC stimulation after myocardial infarction.
PMID:41801224 | DOI:10.1096/fj.202501845RRR