FGF21 overexpression alleviates VSMC senescence in diabetic mice by modulating the SYK-NLRP3 inflammasome-PPARγ-catalase pathway  

作　　者：Yanyan Heng Wei Wei Linzhong Cheng Feifei Wu Haoyu Dong Jingxia Li Jianing Fu Bingjie Yang Xinyue Liang Chunyan Liu Haiju Li Haihua Liu Pengfei Zhang 

机构地区：[1]Department of Nephrology,Heping Hospital Affiliated to Changzhi Medical College,Changzhi 046000,China [2]Department of Pharmacology,Changzhi Medical College,Changzhi 046000,China [3]Department of Endocrinology,Heping Hospital Affiliated to Changzhi Medical College,Changzhi 046000,China [4]Department of Clinical Central Laboratory,Heping Hospital Affiliated to Changzhi Medical College,Changzhi 046000,China [5]Department of National Institute for Clinical Trials of Drugs and Phase I Clinical Trial Laboratory,Heping Hospital Affiliated to Changzhi Medical College,Changzhi 046000,China [6]Department of Anesthesia,Changzhi Medical College,Changzhi 046000,China [7]Department of Stomatology,Changzhi Medical College,Changzhi 046000,China [8]Department of Medical Imageology,Changzhi Medical College,Changzhi 046000,China

出　　处：《Acta Biochimica et Biophysica Sinica》2024年第6期892-904,共13页生物化学与生物物理学报（英文版）

基　　金：supported by the grants from the Projects of Heping Hospital Affiliated to Changzhi Medical College(Nos.HPYJ201921,HPYJ202218,HPYJ202210);the Scientific and Technological Innovation Programs(STIP)of Higher Education Institutions in Shanxi(No.2021L351);the Research Fund of Changzhi Medical College(No.BS202115);the Department of Science and Technology of Shanxi(No.202203021211107);the Health Commission of Shanxi Province(No.2022021).

摘　　要：Diabetes accelerates vascular senescence,which is the basis for atherosclerosis and stiffness.The activation of the NOD-like receptor family pyrin domain containing 3(NLRP3)inflammasome and oxidative stress are closely associated with progressive senescence in vascular smooth muscle cells(VSMCs).The vascular protective effect of FGF21 has gradually gained increasing attention,but its role in diabetes-induced vascular senescence needs further investigation.In this study,diabetic mice and primary VSMCs are transfected with an FGF21 activation plasmid and treated with a peroxisome proliferator-activated receptorγ(PPARγ)agonist(rosiglitazone),an NLRP3 inhibitor(MCC950),and a spleen tyrosine kinase(SYK)-specific inhibitor,R406,to detect senescence-associated markers.We find that FGF21 overexpression significantly restores the level of catalase(CAT),vascular relaxation,inhibits the intensity of ROSgreen fluorescence and p21 immunofluorescence,and reduces the area of SA-β-gal staining and collagen deposition in the aortas of diabetic mice.FGF21 overexpression restores CAT,inhibits the expression of p21,and limits the area of SA-β-gal staining in VSMCs under high glucose conditions.Mechanistically,FGF21 inhibits SYK phosphorylation,the production of the NLRP3 dimer,the expression of NLRP3,and the colocalization of NLRP3 with PYCARD(ASC),as well as NLRP3 with caspase-1,to reverse the cleavage of PPARγ,preserve CAT levels,suppress ROSgreen density,and reduce the expression of p21 in VSMCs under high glucose conditions.Our results suggest that FGF21 alleviates vascular senescence by regulating the SYK-NLRP3 inflammasome-PPARγ-catalase pathway in diabetic mice.

关 键 词：vascular smooth muscle cell SENESCENCE NLRP3 inflammasome PPARγ CATALASE 

分 类 号：R587.1[医药卫生—内分泌]