PAR-1 is a novel mechano-sensor transducing laminar flow-mediated endothelial signaling.
PAR-1 is a novel mechano-sensor transducing laminar flow-mediated endothelial signaling.
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DOI：
10.1038/s41598-018-33222-3
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发表时间：
2018-10-11
影响因子：
4.6
通讯作者：
Woo CH
中科院分区：
文献类型：
--
作者：
Kim S;Han JH;Nam DH;Kim GY;Lim JH;Kim JR;Woo CH
最近的研究表明，蛋白酶激活受体-1（PAR-1）参与内皮细胞（EC）的细胞保护和抗炎反应。然而，PAR-1在层流介导的动脉粥样硬化保护反应中的作用仍然未知。在此，我们研究了PAR-1是否调节EC中层流介导的机械转导。共聚焦分析表明，PAR-1内化到早期内涵体响应层流。此外，流式细胞术分析表明，PAR-1的细胞表面表达减少层流，表明PAR-1被激活响应层流。使用人PAR-1 siRNA消耗PAR-1抑制单向层流介导的肌动蛋白应力纤维形成和细胞排列以及HUVEC中的动脉粥样硬化保护基因表达。此外，PAR-1敲低抑制层流刺激的eNOS磷酸化，并抑制Src，AMPK，ERK 5和HDAC 5的磷酸化。此外，PAR-1耗竭抑制层流介导的抗炎反应，如TNFα诱导的VCAM-1表达减少和单核细胞粘附于HUVEC所示，并阻止层流介导的抗凋亡反应。一项使用小鼠主动脉环研究PAR-1在血管舒张调节中的作用的研究显示，与同窝对照组相比，PAR-1缺陷小鼠中乙酰胆碱诱导的血管舒张减少。综上所述，这些发现表明PAR-1被视为治疗血管疾病，包括动脉粥样硬化的一种新的药理学靶点。
Recent studies have indicated that protease-activated receptor-1 (PAR-1) is involved in cytoprotective and anti-inflammatory responses in endothelial cells (ECs). However, the role of PAR-1 in laminar flow-mediated atheroprotective responses remains unknown. Herein, we investigated whether PAR-1 regulates laminar flow-mediated mechanotransduction in ECs. Confocal analysis showed that PAR-1 was internalized into early endosomes in response to laminar flow. In addition, flow cytometry analysis showed that cell surface expression of PAR-1 was reduced by laminar flow, suggesting that PAR-1 was activated in response to laminar flow. Depletion of PAR-1 using human PAR-1 siRNA inhibited unidirectional laminar flow-mediated actin stress fiber formation and cellular alignment as well as atheroprotective gene expressions in HUVECs. Moreover, PAR-1 knockdown inhibited laminar flow-stimulated eNOS phosphorylation, and inhibited the phosphorylations of Src, AMPK, ERK5 and HDAC5. Furthermore, PAR-1 depletion inhibited laminar flow-mediated anti-inflammatory responses as demonstrated by reduced TNFα-induced VCAM-1 expression and by monocyte adhesion to HUVECs, and prevented laminar flow-mediated anti-apoptotic response. An investigation of the role of PAR-1 in vasomotor modulation using mouse aortic rings revealed that acetylcholine-induced vasorelaxation was diminished in PAR-1 deficient mice compared to littermate controls. Taken together, these findings suggest that PAR-1 be viewed as a novel pharmacologic target for the treatment of vascular diseases, including atherosclerosis.
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影响因子：
3.8
作者：
Heo KS;Fujiwara K;Abe J
通讯作者：
Abe J
影响因子：
4.8
作者：
Kim, I;Moon, SO;Koh, GY
通讯作者：
Koh, GY
影响因子：
64.8
作者：
Dimmeler, S;Fleming, I;Zeiher, AM
通讯作者：
Zeiher, AM
DOI：
10.1073/pnas.83.7.2114
发表时间：
1986-04-01
影响因子：
11.1
作者：
DAVIES, PF;REMUZZI, A;GIMBRONE, MA
通讯作者：
GIMBRONE, MA
DOI：
10.1115/1.3138276
发表时间：
1981-01-01
影响因子：
1.7
作者：
DEWEY, CF;BUSSOLARI, SR;DAVIES, PF
通讯作者：
DAVIES, PF