Protection of beta-blocker and 5-hydroxytryptamine 1A receptor agonist on myocardial ischemia injury in rats by regulating the NLRP3/Caspase-1/GSDMD pathway

Abstract

Objective To explore the effects and related mechanisms of a β-blocker combined with a 5-hydroxytryptamine 1A receptor (5-HT1AR) agonist on MI injuries in rats. Methods TTC/Evans blue, H&E, Masson, and TUNEL staining were used to assess infarction area, pathological damage, fibrosis, and apoptosis in myocardial tissue. The ELISA kits were used to detect IL-1β and IL-18 levels. The immunohistochemical (IHC) staining was used in conjunction with qRT-PCR and Western blot to determine IL-1β, IL-18, NLRP3, pro Caspase-1, cleaved Caspase-1, GSDMD-FL, and GSDMD-N expression levels. Results In myocardial tissue, the β-blocker combined with the 5-HT1AR agonist effectively reduced infarction size, mitigated pathological injury, alleviated fibrosis, and prevented apoptosis. Meanwhile, the β-blocker combined with the 5-HT1AR agonist downregulated IL-1β and IL-18 levels in serum and myocardial tissue. Notably, although it barely altered the expression of the pyroptosis precursor proteins pro Caspase‑1 and GSDMD‑FL, the combined therapy strongly suppressed the mRNA and protein levels of NLRP3, cleaved Caspase‑1, and GSDMD‑N, and reduced the ratios of pro Caspase‑1/cleaved Caspase‑1 and GSDMD-FL/GSDMD-N in myocardial tissue. Conclusion β-blocker combined with the 5-HT1AR agonist relieves MI injuries by suppressing the NLRP3/Caspase-1/GSDMD pathway.