Autophagic degradation of caveolin-1 promotes liver sinusoidal endothelial cells defenestration

Cell Death Dis. 2018 May 1;9(5):576. doi: 10.1038/s41419-018-0567-0.

Abstract

Autophagy, interacting 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. Furthermore, autophagy, degradation of Cav-1, and actin filament (F-actin) remodeling were triggered during the process of CCl4-induced LSECs defenestration; in contrast, autophagy inhibitor 3MA diminished the degradation of Cav-1 to maintain fenestrae and relieve CCl4-induced fibrosis. In vitro, during LSECs defenestration, the NO-dependent pathway was down-regulated through the 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 the 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy*
  • Carbon Tetrachloride / toxicity
  • Carbon Tetrachloride Poisoning / metabolism
  • Carbon Tetrachloride Poisoning / pathology
  • Caveolin 1 / metabolism*
  • Endothelial Cells / metabolism*
  • Endothelial Cells / pathology
  • Female
  • Humans
  • Liver / metabolism*
  • Liver / pathology
  • Liver Cirrhosis / chemically induced
  • Liver Cirrhosis / metabolism*
  • Liver Cirrhosis / pathology
  • MAP Kinase Signaling System / drug effects
  • Male
  • Proteolysis*
  • Rats
  • Rats, Sprague-Dawley

Substances

  • CAV1 protein, human
  • Cav1 protein, rat
  • Caveolin 1
  • Carbon Tetrachloride