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.
Highlights
The liver sinusoidal endothelial cells (LSECs) are characterized with possession of fenestrae, whose disappearance is implicated in liver fibrogenesis and cirrhosis[1,2]
The protein expression of ATG5 and LC3 II/I, as well as the data of transmission electron microscopy (TEM), showed that autophagy was activated in liver sinusoidal endothelium in human liver fibrosis (Fig. 1d, e)
In the present study, we demonstrated that autophagic degradation of Cav-1 promoted F-actin remodeling and inhibited the NO-dependent pathway to aggravate LSECs defenestration via downregulation of the PI3K–AKT–MTOR pathway (Fig 9)
Summary
The liver sinusoidal endothelial cells (LSECs) are characterized with possession of fenestrae, whose disappearance is implicated in liver fibrogenesis and cirrhosis[1,2]. To explore the underlying mechanism and the therapeutic target of chronic liver diseases, scientists concentrate on the promoter of the dysregulation of LSECs phenotype[3]. Actin cytoskeleton (such as F-actin), which are closely affiliated with LSECs fenestration, could regulate the contraction and dilatation of the fenestrae[4,5,6]. The changes and migration of Cav-1 or F-actin remodeling might influence LSECs phenotype. Autophagy is a process that regulates cellular homeostasis and eliminates the damaged proteins or organelles[7,8].
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