期刊
CELL DEATH & DISEASE
卷 10, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41419-019-1375-x
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资金
- Ministry of Education, Culture, Sports, Science, and Technology-Japan [16K15317, 16H04924]
- Grants-in-Aid for Scientific Research [16K15317, 16H04924] Funding Source: KAKEN
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 beta-arrestin-mediated-biased signal transduction. We focused on the effect of beta-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 beta-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 beta-arrestin-2 levels and more severe ischemic injury. The expression of beta-arrestin-2 in capillaries and PDGF-beta secretion in HFD-fed mice were reduced in penumbra lesions. These results suggested that beta-arrestin-2-MAPK-PDGF-beta signaling enhanced protection of endothelial function and barrier integrity after stroke.
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