PAR-1 is a novel mechano-sensor transducing laminar flow-mediated endothelial signaling

Suji Kim, Jung Hwa Han, Dae Hwan Nam, Geun Young Kim, Jae Hyang Lim, Jae Ryong Kim, Chang Hoon Woo

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14 Scopus citations

Abstract

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.

Original languageEnglish
Article number15172
JournalScientific Reports
Volume8
Issue number1
DOIs
StatePublished - 1 Dec 2018

Bibliographical note

Funding Information:
This research was supported by the Medical Research Center Program (2015R1A5A2009124) and Basic Science Research Program (2015R1D1A1A01059398) through the Korean National Research Foundation (NRF) funded by the Ministry of Science, ICT, and Future Planning.

Publisher Copyright:
© 2018, The Author(s).

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