The Role And Mechanism Of Autophagic Degradation Of Caveolin-1 In Liver Sinusoidal Endothelial Cell Defenestration

Autophagy,interacted with actin cytoskeleton and the NO-dependent pathway,may affect the phenotype and function of endothelial cells.Moreover,caveolin-1(Cav-1),as a structure protein in liver sinusoidal endothelial cells(LSECs),is closely related to autophagy.Hence,we aim to explore the role of autophagic degradation of Cav-1 in LSECs defenestration.In vivo,we found the increase of autophagy in liver sinusoidal endothelium in human fibrotic liver.cav-1,Furthermore,autophagy,degradation of Cav-1,and actin filament(F-actin)remodeling were triggered during the process of CC14-induced LSECs defenestration;in contrast,autophagy inhibitor 3MA diminished the degradation of Cav-1 to maintain fenestrae and relieve CC14-induced fibrosis.In vitro,during LSECs defenestration,the NO-dependent pathway was down-regulated through reduction of the PI3K-AKT-MTOR pathway and initiation of autophagic degradation of Cav-1;while,these effects were aggravated by starvation.However,VEGF inhibited autophagic degradation of Cav-1 and F-actin remodeling to maintain LSECs fenestrae via activating the PI3K-AKT-MTOR pathway.Additionally,inhibiting autophagy,such as 3MA,bafilomycin or ATG5-siRNA,could attenuate the depletion of Cav-1 and F-actin remodeling to maintain LSECs fenestrae and improve the NO-dependent pathway;in turn,eNOS-siRNA and L-NAME,for blocking the NO-dependent pathway,could elevate autophagic degradation of Cav-1 to aggravate defenestration.Finally,overexpressed Cav-1 rescued rapamycin-induced autophagic degradation of Cav-1 to maintain LSECs fenestrae;whereas knockdown of Cav-1 facilitated defenestration due to activation of the AMPK-dependent autophagy.Consequently,autophagic degradation of Cav-1 promotes LSECs defenestration via inhibiting the NO-dependent pathway and F-actin remodeling.