恩格列净通过KEAP1/NRF2轴抑制巨噬细胞焦亡进而延缓动脉粥样硬化进展

Empagliflozin inhibits macrophage pyrolysis through KEAP1/NRF2 axis and delays progression of atherosclerosis

目的探究恩格列净通过KEAP1/NRF2轴抑制巨噬细胞焦亡进而延缓动脉粥样硬化进展。方法选择2021年6月—2022年6月在本院治疗的糖尿病患者49例,给予恩格列净治疗,观测患者血糖血脂、中性粒细胞及外周炎性因子水平变化情况;检测巨噬细胞活力及焦亡状况以及焦亡相关基因、蛋白表达情况;取小鼠动脉及外周血观察动脉粥样硬化面积及焦亡相关蛋白表达情况。结果患者血糖血脂明显低于使用恩格列净前(P<0.05);TNFα、IL-1β及CRP水平较使用前低(P<0.05);oxldl+恩格列净组相较于Oxldl组,巨噬细胞死亡量减少(P<0.05),NLRP3、Caspase1、GSDMD及IL-1β的mRNA表达水平均降低(P<0.05),NRF2在巨噬细胞核中表达水平升高(P<0.05);高脂饮食+恩格列净组相较于高脂饮食组,小鼠动脉粥样硬化面积较小(P<0.05),并且DAPI、MAC-3、NLRP3及Merge表达水平均较低(P<0.05)。结论推测恩格列净可与KEAP1竞争性结合NRF2,从而抑制巨噬细胞焦亡。

Objective This paper aims to investigate the inhibition of empagliflozin on macrophage pyrolysis through KEAP1/NRF2 axis and its delaying on the progression of atherosclerosis.Methods Forty nine diabetic patients who were treated in our hospital from June 2021 to June 2022 were selected and treated with empagliflozin,and the changes in the levels of blood glu⁃cose,blood lipids,neutrophils and peripheral inflammatory factors were observed.Macrophage viability and pyroptosis status,and the expression of pyroptosis related genes and proteins were detected.The atherosclerotic area and the expression of pyropto⁃sis related proteins were observed in the arteries and peripheral blood of mice.Results The blood glucose and blood lipids of the patients were significantly lower than those before the use of empagliflozin(P<0.05);the levels of TNFα,IL-1βand CRP were lower than those before the use of empagliflozin(P<0.05).The amount of cell death decreased in oxldl+empagli⁃flozin group than that in Oxldl group(P<0.05).The mRNA levels of NLRP3,Caspase1,GSDMD and IL-1βwere decreased(P<0.05),and the level of NRF2 in macrophage nucleus was increased(P<0.05).Compared with the high-fat diet group,the atherosclerotic area of mice in high fat diet+empagliflozin group was smaller(P<0.05),and the levels of DAPI,MAC-3,NLRP3 and Merge were lower(P<0.05).Conclusion It was determined that empagliflozin can compete with KEAP1 for binding to NRF2,thereby inhibiting macrophage pyrolysis.