脂联素/APPL1轴调控紧密连接减轻糖尿病血管内皮细胞损伤OA

Objective To investigate the downstream molecular mechanisms by which the adiponectin(APN)/APPL1 signaling axis alleviates diabetic vascular endothelial injury.Methods APPL1-knockout diabetic mice were treated with APN.Hindlimb ischemia models were established to evaluate vascular regeneration.Endothelial injury and apoptosis were assessed by Western blot and caspase-3 activity.Human umbilical vein endothelial cells(HU-VECs)were transfected with APPL1 siRNA to examine the effects of APN on apoptosis and permeability.Tran-scriptomic profiling was performed followed by GO and KEGG enrichment analyses.Selected targets were validated by RT-qPCR.Results APN markedly improved hindlimb blood flow recovery,increased CD31 expression and suppressed caspase-3 activity in diabetic mice,whereas these protective effects were completely abrogated in the absence of APPL1(P＜0.01).Consistently,in HUVECs,APN reduced high glucose/high lipid-induced apoptosis and permeability,but APPL1 silencing abolished these injury-suppressive effects(P＜0.01).Transcriptomic analysis identified 1 559 genes regulated by the APN/APPL1 signaling axis,predominantly enriched in tight junc-tions,cell adhesion and Hippo signaling pathways.Validation studies highlighted Occludin,a central tight junction protein,whose expression was strictly dependent on APPL1.Conclusions APN alleviates diabetic vascular endo-thelial injury through an APPL1-dependent signaling mechanism,with Occludin emerging as a pivotal downstream molecular target.