A Ganoderma lingzhi peptide attenuated cardiac inflammatory response during ischemia-reperfusion by modulating arginine biosynthesis and inhibiting NLRP3-dependent pyroptosis

Mushrooms have received an attention as one of functional food resources that are rich in polysaccharides and peptides. This study aims to explore the protective effect of Ganoderma lingzhi peptide GLP4 on myocardial I/R injury and its potential molecular mechanism. In this work, we found that GLP4 ameliorates myocardial I/R injury by modulating the inflammatory response. GLP4 significantly improved the area of myocardial infarction, inhibited myocardial dysfunction caused by I/R injury, and restored cardiac function indexes such as ejection fraction (EF), shortening fraction (FS). In addition, GLP4 improved NO level, inhibited iNOS expression, and suppressed the expression of chemokines and inflammatory factors to inhibit cardiac inflammatory response. The intake of GLP4 significantly changed the abundance of 17 metabolites, including L-arginine and α-Ketoglutaric acid (α-KG). In addition, transcriptomics showed that GLP4 reversed 116 differentially changed genes after I/R injury, and downregulated multiple inflammatory response signaling pathways, affected the NLRP3 complex. In vivo and in vitro, GLP4 down-regulated the expression of NLRP3 inflammasome-associated protein and inhibits pyroptosis. Omics analysis showed that GLP4 mainly regulated arginine biosynthesis, arginine and proline metabolism, and D-glutamine and D-glutamate metabolism. This process was significantly regulated by iNOS/NF-κB. These results suggest that the protective effect of GLP4 mainly depends on promoting arginine biosynthesis and inhibiting the NF-κB/NLRP3/Caspase-1/GSDMD signaling pathway to improve myocardial I/R injury.