β-arrestin-2 in PAR-1-biased Signaling Has a Crucial Role in Endothelial Function Via PDGF-β in Stroke

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2019 Feb 6

PMID 30718498

Citations 9

Authors

Hideaki Kanki

Tsutomu Sasaki

Shigenobu Matsumura

Satoru Yokawa

Toshiro Yukami

Munehisa Shimamura

Manabu Sakaguchi

Tadahide Furuno

Takahiro Suzuki

Hideki Mochizuki

Affiliations

Soon will be listed here.

Abstract

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.

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