Mechanism of total glucosides of paeony in hypoxia/reoxygenation-induced cardiomyocyte pyroptosis

Abstract

Inflammasome-mediated pyroptosis can aggravate myocardial ischemia/reperfusion injury. Total glucosides of paeony (TGP) is widely used in anti-inflammation. This study investigated the effect of TGP on pyroptosis of hypoxia/reoxygenation (H/R)-induced cardiomyocytes. HL-1 cells were subjected to H/R treatment. H/R-induced cardiomyocytes were treated with TGP at different concentrations (50, 100, and 200 mg/kg). The viability of H/R-induced cardiomyocytes was measured. The levels of lactate dehydrogenase (LDH), malondialdehyde (MDA), superoxide dismutase (SOD), and reactive oxygen species (ROS) were determined. The activity of caspase-1, the expressions of NLRP3 and GSDMD-N, and the concentrations of IL-1β and IL-18 were examined. miR-181a-5p expression in H/R cardiomyocytes was determined. The targeting relationship between miR-181a-5p and adenylate cyclase 1 (ADCY1) was verified. Functional rescue experiments were performed to verify the effect of miR-181a-5p or ADCY1 on the pyroptosis of H/R cardiomyocytes. TGP enhanced H/R-induced cardiomyocyte viability in a dose-dependent manner, reduced LDH, MDA, and ROS levels, increased SOD level, decreased caspase-1 activity, reduced NLRP3 and GSDMD-N expressions, and inhibited IL-1β and IL-18 concentrations. TGP suppressed miR-181a-5p expression in H/R cardiomyocytes. miR-181a-5p targeted ADCY1. miR-181a-5p overexpression or ADCY1 inhibition reversed the inhibitory effect of TGP on the pyroptosis of H/R cardiomyocytes. Collectively, TGP alleviated the pyroptosis of H/R cardiomyocytes via the miR-181a-5p/ADCY1 axis.

Keywords: ADCY1; Cardiomyocytes; Hypoxia/reoxygenation; Inflammatory injury; Total glucosides of paeony; miR-181a-5p.