Geniposide alleviates post-myocardial infarction-induced pyroptosis by modulating the thioredoxin-interacting protein/NLRP3 signaling pathway.

Abstract

Objective: Geniposide (GP) provides myocardial cells with protection against pyroptosis-induced damage. However, the mechanisms governing GP's effect on the thioredoxin-interacting protein (TXNIP)/nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) signaling pathway remain unclear. This study aimed to explore how GP alleviates post-myocardial infarction (MI)-induced pyroptosis through regulation of the TXNIP/NLRP3 pathway.

Material and methods: In vivo studies: MI models were established, mouse body weight, heart rate, and blood glucose levels were monitored, and methods, such as cardiac ultrasound, hematoxylin-eosin staining, triphenyltetrazolium chloride staining, terminal deoxynucleotidyl transferase 2'-deoxyuridine 5'-triphosphate nick end labeling staining, quantitative polymerase chain reaction (qPCR), and Western blot (WB), were used to explore the effect of GP on myocardial cell pyroptosis. We explored the role of NLRP3 in GP's antimyocardial cell pyroptosis through qPCR, WB, immunofluorescence, enzyme-linked immunosorbent assay (ELISA), and other methods. In vitro studies: A chronic hypoxia (CH) cell model was established, and detection methods, such as cell counting kit-8 assay, transmission electron microscopy, ELISA, and immunological assays, were used to explore the effects of GP on CH myocardial cell pyroptosis and GP's inhibition of the TXNIP/NLRP3 signaling pathway to resist CH myocardial cell pyroptosis.

Results: In vivo studies revealed that after the treatment with GP, the infarct area of mice's hearts significantly decreased, cardiac structure and function notably improved, fibroblast proliferation in cardiac tissues decreased significantly, and the pyroptosis level of myocardial cells decreased. GP treatment significantly downregulated the expression levels of type I collagen (Col I), Col III, TXNIP NLRP3, caspase-1, and gasdermin D N-terminal (GSDMD-N). The inhibition of NLRP3 also reduced the expressions of NLRP3, TXNIP, caspase-1, and GSDMD-N in the cardiac tissue, which is concomitant with a decline in reactive oxygen species (ROS) production. In addition, in vitro studies unveiled that GP effectively alleviated pyroptosis in CH myocardial cells, reducing pyroptosis rates, interleukin (IL)-1β, IL-18, lactate dehydrogenase, and creatine kinase-muscle/brain levels. This protective effect was achieved by inhibiting the TXNIP/NLRP3 signaling pathway.

Conclusion: GP greatly diminishes the extent of infarcted myocardial tissue and mitigates pyroptosis, which improves cardiac structure and function through modulation of the TXNIP/NLRP3 pathway. Furthermore, the inhibition of NLRP3 lowers the expressions of factors associated with pyroptosis in the cardiac tissue and reduces ROS production.