Macrophages regulate plaque progression in diabetic Apoe-/- mice dependent on Pi4p/Nlrp3 signaling pathway

Background and aims Atherosclerotic cardiovascular disease complicated by diabetes mellitus (DM) is the leading cause of death in diabetic patients, and it is strongly associated with macrophages and inflammasomes. It has been found that activation of NLRP3 inflammasome is closely associated with phosphatidylinositol 4-phosphate (PI4P) on the trans-Golgi. However, how PI4P and NLRP3 regulate macrophage function and its role in diabetic atherosclerotic plaques is unclear. Methods The expression of Pi4p and Nlrp3-inflammasome-related proteins in atherosclerosis in apolipoprotein E-deficient ( Apoe -/- ) and Apoe -/- DM mice were investigated. Then, Pi4p levels were affected by shRNA-Pi4kb or cDNA-Sac1 plasmid to investigate the effects of changes in Pi4p-related metabolic enzymes on macrophage function. Finally, the genetically modified macrophages were injected into diabetic Apoe -/- mice to explore their effects on the pathology of atherosclerosis. Results DM promoted plaque progression in atherosclerotic mice and increased expression of Pi4p and Nlrp3 on plaques. In addition, impaired macrophage function induced by high glucose was reversed by transfected shRNA-Pi4kb or cDNA-Sac1 plasmid. Furthermore, it was demonstrated that decreased levels of Pi4p reduced plaque area in diabetic Apoe -/- mice. Conclusions Taken together, our data suggested that Pi4p/Nlrp3 in macrophages plays an important role in the exacerbation of atherosclerosis in diabetic mice. Pi4p-related metabolizing enzymes (PI4KB and SAC1) may be the potential therapeutic strategy for diabetic atherosclerosis, and macrophage therapy is also a potential treatment.