Open Accessβ-arrestin-2 in PAR-1-biased signaling has a crucial role in endothelial function via PDGF-β in stroke
Author(s) -
Hideaki Kanki,
Tsutomu Sasaki,
Shigenobu Matsumura,
Satoru Yokawa,
Toshiro Yukami,
Munehisa Shimamura,
Manabu Sakaguchi,
Tadahide Furuno,
Takahiro Suzuki,
Hideki Mochizuki
Publication year - 2019
Publication title -
cell death and disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.482
H-Index - 111
ISSN - 2041-4889
DOI - 10.1038/s41419-019-1375-x
Subject(s) - microbiology and biotechnology , function (biology) , platelet derived growth factor receptor , signal transduction , stroke (engine) , neuroscience , biology , medicine , growth factor , receptor , physics , thermodynamics
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.