ChloroquineV1, Main, Exploration, bibRecord, 000172

Degradation of group V secretory phospholipase A2 in lung endothelium is mediated by autophagy.

Identifieur interne : 000172 ( Main/Exploration ); précédent : 000171; suivant : 000173

Degradation of group V secretory phospholipase A2 in lung endothelium is mediated by autophagy.

Auteurs : Lucille N. Meliton [États-Unis] ; Xiangdong Zhu [États-Unis] ; Mary Brown [États-Unis] ; Yulia Epshtein [États-Unis] ; Takeshi Kawasaki [Japon] ; Eleftheria Letsiou [États-Unis] ; Steven M. Dudek [États-Unis]

Source :

Microvascular research [ 1095-9319 ] ; 2020.

RBID : pubmed:31730773

Abstract

Group V secretory phospholipase A₂ (gVPLA₂) is a potent inflammatory mediator in mammalian tissues that hydrolyzes phospholipids and initiates eicosanoid biosynthesis. Previous work has demonstrated that multiple inflammatory stimuli induce its expression and secretion in several cell types, including the lung endothelium. However, little is known about the mechanism(s) by which gVPLA₂ inflammatory signaling is subsequently downregulated. Therefore, in this study we characterized potential clearance mechanisms for gVPLA₂ in lung endothelial cells (EC). We observed that exogenous gVPLA₂ is taken up rapidly by nutrient-starved human pulmonary artery EC (HPAEC) in vitro, and its cellular expression subsequently is reduced over several hours. In parallel experiments performed in pulmonary vascular EC isolated from mice genetically deficient in gVPLA₂, the degradation of exogenously applied gVPLA₂ occurs in a qualitatively similar fashion. This degradation is significantly attenuated in EC treated with ammonium chloride or chloroquine, which are lysosomal inhibitors that block autophagic flux. In contrast, the proteasomal inhibitor MG132 fails to prevent the clearance of gVPLA₂. Both immunofluorescence microscopy and proximity ligation assay demonstrate the co-localization of LC3 and gVPLA₂ during this process, indicating the association of gVPLA₂ with autophagosomes. Nutrient starvation, a known inducer of autophagy, is sufficient to stimulate gVPLA₂ degradation. These results suggest that a lysosome-mediated autophagy pathway contributes to gVPLA₂ clearance from lung EC. These novel observations advance our understanding of the mechanism by which this key inflammatory enzyme is downregulated in the lung vasculature.

DOI: 10.1016/j.mvr.2019.103954
PubMed: 31730773

Affiliations:

Le document en format XML

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<front><div type="abstract" xml:lang="en">Group V secretory phospholipase A<sub>2</sub>
 (gVPLA<sub>2</sub>
) is a potent inflammatory mediator in mammalian tissues that hydrolyzes phospholipids and initiates eicosanoid biosynthesis. Previous work has demonstrated that multiple inflammatory stimuli induce its expression and secretion in several cell types, including the lung endothelium. However, little is known about the mechanism(s) by which gVPLA<sub>2</sub>
 inflammatory signaling is subsequently downregulated. Therefore, in this study we characterized potential clearance mechanisms for gVPLA<sub>2</sub>
 in lung endothelial cells (EC). We observed that exogenous gVPLA<sub>2</sub>
 is taken up rapidly by nutrient-starved human pulmonary artery EC (HPAEC) in vitro, and its cellular expression subsequently is reduced over several hours. In parallel experiments performed in pulmonary vascular EC isolated from mice genetically deficient in gVPLA<sub>2</sub>
, the degradation of exogenously applied gVPLA<sub>2</sub>
 occurs in a qualitatively similar fashion. This degradation is significantly attenuated in EC treated with ammonium chloride or chloroquine, which are lysosomal inhibitors that block autophagic flux. In contrast, the proteasomal inhibitor MG132 fails to prevent the clearance of gVPLA<sub>2</sub>
. Both immunofluorescence microscopy and proximity ligation assay demonstrate the co-localization of LC3 and gVPLA<sub>2</sub>
 during this process, indicating the association of gVPLA<sub>2</sub>
 with autophagosomes. Nutrient starvation, a known inducer of autophagy, is sufficient to stimulate gVPLA<sub>2</sub>
 degradation. These results suggest that a lysosome-mediated autophagy pathway contributes to gVPLA<sub>2</sub>
 clearance from lung EC. These novel observations advance our understanding of the mechanism by which this key inflammatory enzyme is downregulated in the lung vasculature.</div>
</front>
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Degradation of group V secretory phospholipase A2 in lung endothelium is mediated by autophagy.

Degradation of group V secretory phospholipase A2 in lung endothelium is mediated by autophagy.

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