β-arrestin-2 in PAR-1-biased signaling has a crucial role in endothelial function via PDGF-β in stroke
β-arrestin-2 in PAR-1-biased signaling has a crucial role in endothelial function via PDGF-β in stroke
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DOI：
10.1038/s41419-019-1375-x
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发表时间：
2019-02-04
影响因子：
9
通讯作者：
Mochizuki, Hideki
中科院分区：
文献类型：
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作者：
Kanki, Hideaki;Sasaki, Tsutomu;Mochizuki, Hideki
凝血酶加重缺血性卒中，活化蛋白C(APC)具有神经保护作用。这两种酶都与蛋白酶激活的受体1相互作用，表现出功能选择性，并导致G蛋白和β-arrestin介导的偏向信号转导。我们重点研究了β-arrestin在PAR-1偏向信号通路中对卒中或高脂饮食(HFD)后血管内皮功能的影响。凝血酶对内皮功能的破坏作用较快，而APC的保护作用较慢。在APC通过β-arrestin-2延长MAPK 42/44信号激活的同时，生物发光视频成像定量显示APC对PAR-1的裂解率低于凝血酶。高脂饲料喂养的小鼠表现出较低的β-arrestin-2水平和更严重的缺血性损伤。半影区毛细血管β-arrestin-2表达和PDGF-β分泌减少。这些结果表明，β-arrestin-2-MAPK-PDGF-beta信号增强了对卒中后内皮功能和屏障完整性的保护。
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.