Abstract
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.
基金项目
Projects of Heping Hospital Affiliated to Changzhi Medical College(HPYJ201921)
Projects of Heping Hospital Affiliated to Changzhi Medical College(HPYJ202218)
Projects of Heping Hospital Affiliated to Changzhi Medical College(HPYJ202210)
Scientific and Technological Innovation Programs(STIP)of Higher Education Institutions in Shanxi(2021L351)
Research Fund of Changzhi Medical College(BS202115)
Department of Science and Technology of Shanxi(202203021211107)
Health Commission of Shanxi Province(2022021)
国家科技期刊平台
NSTL
万方数据