PAR-1 is a Novel Mechano-sensor Transducing Laminar Flow-mediated Endothelial Signaling

Overview

Journal Sci Rep

Specialty Science

Date 2018 Oct 13

PMID 30310081

Citations 7

Authors

Suji Kim

Jung-Hwa Han

Dae-Hwan Nam

Geun-Young Kim

Jae Hyang Lim

Jae-Ryong Kim

Chang-Hoon Woo

Affiliations

Soon will be listed here.

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.

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References

Wang S, Iring A, Strilic B, Albarran Juarez J, Kaur H, Troidl K . P2Y₂ and Gq/G₁₁ control blood pressure by mediating endothelial mechanotransduction. J Clin Invest. 2015; 125(8):3077-86. PMC: 4563756. DOI: 10.1172/JCI81067. View

Kim I, Moon S, Kim S, Kim H, Koh Y, Koh G . Vascular endothelial growth factor expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin through nuclear factor-kappa B activation in endothelial cells. J Biol Chem. 2000; 276(10):7614-20. DOI: 10.1074/jbc.M009705200. View

Dewey Jr C, Bussolari S, Gimbrone Jr M, Davies P . The dynamic response of vascular endothelial cells to fluid shear stress. J Biomech Eng. 1981; 103(3):177-85. DOI: 10.1115/1.3138276. View

Fleming I, Fisslthaler B, Dixit M, Busse R . Role of PECAM-1 in the shear-stress-induced activation of Akt and the endothelial nitric oxide synthase (eNOS) in endothelial cells. J Cell Sci. 2005; 118(Pt 18):4103-11. DOI: 10.1242/jcs.02541. View

Balaguru U, Sundaresan L, Manivannan J, Majunathan R, Mani K, Swaminathan A . Disturbed flow mediated modulation of shear forces on endothelial plane: A proposed model for studying endothelium around atherosclerotic plaques. Sci Rep. 2016; 6:27304. PMC: 4891674. DOI: 10.1038/srep27304. View

Jo H, Sipos K, Go Y, Law R, Rong J, McDonald J . Differential effect of shear stress on extracellular signal-regulated kinase and N-terminal Jun kinase in endothelial cells. Gi2- and Gbeta/gamma-dependent signaling pathways. J Biol Chem. 1997; 272(2):1395-401. DOI: 10.1074/jbc.272.2.1395. View

Li Y, Haga J, Chien S . Molecular basis of the effects of shear stress on vascular endothelial cells. J Biomech. 2005; 38(10):1949-71. DOI: 10.1016/j.jbiomech.2004.09.030. View

Hamilton J, Cocks T . Heterogeneous mechanisms of endothelium-dependent relaxation for thrombin and peptide activators of protease-activated receptor-1 in porcine isolated coronary artery. Br J Pharmacol. 2000; 130(1):181-8. PMC: 1572028. DOI: 10.1038/sj.bjp.0703146. View

Cendrowski J, Maminska A, Miaczynska M . Endocytic regulation of cytokine receptor signaling. Cytokine Growth Factor Rev. 2016; 32:63-73. DOI: 10.1016/j.cytogfr.2016.07.002. View

10.

Li S, Kim M, Hu Y, Jalali S, Schlaepfer D, Hunter T . Fluid shear stress activation of focal adhesion kinase. Linking to mitogen-activated protein kinases. J Biol Chem. 1997; 272(48):30455-62. DOI: 10.1074/jbc.272.48.30455. View

11.

Malek A, Alper S, Izumo S . Hemodynamic shear stress and its role in atherosclerosis. JAMA. 1999; 282(21):2035-42. DOI: 10.1001/jama.282.21.2035. View

12.

Tsvetanova N, Irannejad R, Von Zastrow M . G protein-coupled receptor (GPCR) signaling via heterotrimeric G proteins from endosomes. J Biol Chem. 2015; 290(11):6689-96. PMC: 4358092. DOI: 10.1074/jbc.R114.617951. View

13.

Traub O, Berk B . Laminar shear stress: mechanisms by which endothelial cells transduce an atheroprotective force. Arterioscler Thromb Vasc Biol. 1998; 18(5):677-85. DOI: 10.1161/01.atv.18.5.677. View

14.

Xiao Y, Morice A, Compton S, Sadofsky L . N-linked glycosylation regulates human proteinase-activated receptor-1 cell surface expression and disarming via neutrophil proteinases and thermolysin. J Biol Chem. 2011; 286(26):22991-3002. PMC: 3123067. DOI: 10.1074/jbc.M110.204271. View

15.

Bae J, Yang L, Manithody C, Rezaie A . The ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells. Blood. 2007; 110(12):3909-16. PMC: 2190610. DOI: 10.1182/blood-2007-06-096651. View

16.

Nigro P, Abe J, Woo C, Satoh K, McClain C, ODell M . PKCzeta decreases eNOS protein stability via inhibitory phosphorylation of ERK5. Blood. 2010; 116(11):1971-9. PMC: 3173991. DOI: 10.1182/blood-2010-02-269134. View

17.

Tzima E, Irani-Tehrani M, Kiosses W, Dejana E, Schultz D, Engelhardt B . A mechanosensory complex that mediates the endothelial cell response to fluid shear stress. Nature. 2005; 437(7057):426-31. DOI: 10.1038/nature03952. View

18.

Kim M, Kim S, Lim J, Lee C, Choi H, Woo C . Laminar flow activation of ERK5 protein in vascular endothelium leads to atheroprotective effect via NF-E2-related factor 2 (Nrf2) activation. J Biol Chem. 2012; 287(48):40722-31. PMC: 3504785. DOI: 10.1074/jbc.M112.381509. View

19.

McKinsey T, Zhang C, Olson E . Activation of the myocyte enhancer factor-2 transcription factor by calcium/calmodulin-dependent protein kinase-stimulated binding of 14-3-3 to histone deacetylase 5. Proc Natl Acad Sci U S A. 2000; 97(26):14400-5. PMC: 18930. DOI: 10.1073/pnas.260501497. View

20.

Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher A . Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature. 1999; 399(6736):601-5. DOI: 10.1038/21224. View