β-arrestin-2 in PAR-1-biased signaling has a crucial role in endothelial function via PDGF-β in stroke.
Hideaki KankiTsutomu SasakiShigenobu MatsumuraSatoru YokawaToshiro YukamiMunehisa ShimamuraManabu SakaguchiTadahide FurunoTakahiro SuzukiHideki MochizukiPublished in: Cell death & disease (2019)
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.
Keyphrases
- high fat diet
- insulin resistance
- adipose tissue
- signaling pathway
- smooth muscle
- high fat diet induced
- atrial fibrillation
- vascular smooth muscle cells
- oxidative stress
- cerebral ischemia
- type diabetes
- binding protein
- early onset
- small molecule
- skeletal muscle
- cell proliferation
- mass spectrometry
- amino acid
- pi k akt
- angiotensin ii
- sensitive detection