β-arrestin-2 in PAR-1-biased signaling has a crucial role in endothelial function via PDGF-β in stroke.
Animals
Cattle
Cells, Cultured
Endothelial Cells
/ enzymology
HEK293 Cells
Human Umbilical Vein Endothelial Cells
/ metabolism
Humans
Luminescent Measurements
MAP Kinase Kinase 2
/ metabolism
Male
Mice
Mice, Inbred C57BL
Neovascularization, Pathologic
/ metabolism
Phosphorylation
Protein C
/ metabolism
Proto-Oncogene Proteins c-sis
/ genetics
Receptor, PAR-1
/ genetics
Recombinant Proteins
/ metabolism
Signal Transduction
/ drug effects
Stroke
/ enzymology
Thrombin
/ metabolism
Time Factors
beta-Arrestin 2
/ genetics
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
04 02 2019
04 02 2019
Historique:
received:
14
05
2018
accepted:
15
01
2019
revised:
07
01
2019
entrez:
6
2
2019
pubmed:
6
2
2019
medline:
9
4
2020
Statut:
epublish
Résumé
Thrombin aggravates ischemic stroke and activated protein C (APC) has a neuroprotective effect. Both proteases interact with protease-activated receptor 1, which exhibits functional selectivity and leads to G-protein- and β-arrestin-mediated-biased signal transduction. We focused on the effect of β-arrestin in PAR-1-biased signaling on endothelial function after stroke or high-fat diet (HFD). Thrombin had a rapid disruptive effect on endothelial function, but APC had a slow protective effect. Paralleled by prolonged MAPK 42/44 signaling activation by APC via β-arrestin-2, a lower cleavage rate of PAR-1 for APC than thrombin was quantitatively visualized by bioluminescence video imaging. HFD-fed mice showed lower β-arrestin-2 levels and more severe ischemic injury. The expression of β-arrestin-2 in capillaries and PDGF-β secretion in HFD-fed mice were reduced in penumbra lesions. These results suggested that β-arrestin-2-MAPK-PDGF-β signaling enhanced protection of endothelial function and barrier integrity after stroke.
Identifiants
pubmed: 30718498
doi: 10.1038/s41419-019-1375-x
pii: 10.1038/s41419-019-1375-x
pmc: PMC6361911
doi:
Substances chimiques
Protein C
0
Proto-Oncogene Proteins c-sis
0
Receptor, PAR-1
0
Recombinant Proteins
0
beta-Arrestin 2
0
MAP Kinase Kinase 2
EC 2.7.12.2
Thrombin
EC 3.4.21.5
drotrecogin alfa activated
JGH8MYC891
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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