Background
Heart failure (HF) is a syndrome with complex etiology and high mortality in the world. Macrophage-related inflammation is involved in HF development. O-GlcNAcylation is a post-translational modification that affects pathological processes. This study aimed to investigate the role of O-GlcNAcylation in HF, especially its effect on macrophage polarization.
Conclusion
Silencing of OGT promotes macrophage polarization from pro-inflammatory to anti-inflammatory phenotype to alleviate HF through O-GlcNAcylation of IRF1. The findings suggest that O-GlcNAcylation has the potential to treat HF.
Methods
Raw264.7 cells were treated with lipopolysaccharide (LPS) to induce pro-inflammatory macrophages. HF mice were generated by transverse aortic constriction (TAC). After knockdown of OGT or overexpressing IRF1, macrophage polarization was evaluated using quantitative real-time polymerase chain reaction and flow cytometry. Underlying mechanism was analyzed using bioinformatic analysis, co-immunoprecipitation (co-IP), IP, and western blotting.
Results
The results showed that O-GlcNAcylation and OGT levels were high in LPS-treated Raw264.7 cells. OGT knockdown inhibited pro-inflammatory macrophage polarization and promoted anti-inflammatory macrophage polarization caused by LPS, and alleviated TAC-induced cardiac dysfunction and fibrosis. Mechanistically, OGT silence suppressed O-GlcNAcylation of IRF1 at Ser (S)283 site. IRF1 overexpression reversed macrophage polarization modulated by OGT knockdown.