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

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外文摘要：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 as-sociated 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 receptor y(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.

外文关键词：

vascular smooth muscle cellsenescenceNLRP3 inflammasomePPARγcatalase

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

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作者单位：

Department of Nephrology,Heping Hospital Affiliated to Changzhi Medical College,Changzhi 046000,China

Department of Pharmacology,Changzhi Medical College,Changzhi 046000,China

Department of Endocrinology,Heping Hospital Affiliated to Changzhi Medical College,Changzhi 046000,China

Department of Clinical Central Laboratory,Heping Hospital Affiliated to Changzhi Medical College,Changzhi 046000,China

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

Department of Anesthesia,Changzhi Medical College,Changzhi 046000,China

Department of Stomatology,Changzhi Medical College,Changzhi 046000,China

Department of Medical Imageology,Changzhi Medical College,Changzhi 046000,China

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基金：

Projects of Heping Hospital Affiliated to Changzhi Medical CollegeProjects of Heping Hospital Affiliated to Changzhi Medical CollegeProjects of Heping Hospital Affiliated to Changzhi Medical CollegeScientific and Technological Innovation Programs(STIP)of Higher Education Institutions in ShanxiResearch Fund of Changzhi Medical CollegeDepartment of Science and Technology of ShanxiHealth Commission of Shanxi Province

项目编号：

HPYJ201921HPYJ202218HPYJ2022102021L351BS2021152022030212111072022021

出版年：

2024

DOI：

10.3724/abbs.2024032

生物化学与生物物理学报(英文版)

中国科学院上海生物化学研究所

生物化学与生物物理学报(英文版)

CSTPCD

影响因子：0.772

ISSN：1672-9145

年,卷(期)：2024.56(6)

参考文献量52