Protective mechanism of nicorandil on myocardial ischemia-reperfusion injury: a multi-omics study highlighting CYP4F5 as a key node.

BACKGROUND

Nicorandil, a vasodilator, exhibits potential in improving myocardial blood supply, but its protective mechanism against myocardial ischemia-reperfusion (I/R) injury remains unclear. This study aims to explore the cardioprotective effects of nicorandil on myocardial I/R injury and elucidate its molecular mechanisms, providing a theoretical basis for clinical treatment.

METHODS

Myocardial I/R injury models were established using SPF-grade male Sprague-Dawley (SD) rats, randomly divided into control, I/R, and I/R+Nicorandil groups (n = 6 per group). The I/R+Nicorandil group, nicorandil (5 mg/kg) was injected intraperitoneally every day from 3 days before the establishment of myocardial I/R model. Myocardial injury was assessed through TTC staining, hematoxylin-eosin (HE) staining, and multi-omics analyses (transcriptome sequencing, proteomics, and metabolomics) to investigate alterations at genetic, protein, and metabolite levels.

RESULTS

Biochemical and histological analyses revealed that nicorandil significantly reduced serum levels of lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and creatine kinase (CK), while decreasing myocardial infarction area and pathological damage. Transcriptome sequencing identified differentially expressed genes (DEGs) enriched in TNF and chemokine signaling pathways between control vs. I/R and I/R vs. I/R+Nicorandil groups. Proteomics analysis screened differentially expressed proteins (DEPs) primarily involved in glycolysis and protein glycosylation. Metabolomics detected two key differential metabolites in positive ion mode. Multi-omics integrative analysis identified CYP4F5 as a pivotal protein node, showing significant correlations with multiple metabolites. Western blot results demonstrated that nicorandil modulated the expression of PPAR-α, NF-κB, cGAS, and STING pathway proteins in myocardial I/R injury.

CONCLUSION

Nicorandil may alleviate myocardial I/R injury by regulating CYP4F5-associated metabolites and signaling pathways.