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Dabigatran reduces endothelial permeability through inhibition of thrombin-induced cytoskeleton reorganization.

Authors
 Hyun-Jung Choi  ;  Na-Eun Kim  ;  Jayoung Kim  ;  Sunho An  ;  Seung-Hee Yang  ;  Jimin Ha  ;  Sunghee Cho  ;  Il Kwon  ;  Young Dae Kim  ;  Hyo Suk Nam  ;  Ji Hoe Heo 
Citation
 Thrombosis Research, Vol.167 : 165-171, 2018 
Journal Title
 Thrombosis Research 
ISSN
 0049-3848 
Issue Date
2018
Keywords
Actin cytoskeleton ; Dabigatran ; Endothelial permeability ; Myosin light chain ; Thrombin
Abstract
Dabigatran etexilate (DE), a new oral anti-coagulant, is a direct thrombin inhibitor. Clinical trials showed the favorable benefit-to-risk profile of DE compared to warfarin for the prevention of ischemic stroke in patients with atrial fibrillation. Remarkably, patients treated with dabigatran showed reduced rates of intracerebral hemorrhage compared to warfarin. As the breakdown of endothelial barrier integrity is associated with hemorrhagic events and as thrombin increases endothelial permeability, we hypothesized that dabigatran preserves the endothelial barrier by inhibiting thrombin-induced permeability. We assessed leakage of fluorescein isothiocyanate (FITC)-dextran through the endothelial monolayer and measured trans-endothelial electrical resistance of the endothelial monolayer after treatment of thrombin or thrombin pre-incubated with dabigatran. Thrombin increased the permeability of endothelial cells. Dabigatran effectively blocked the ability of thrombin to increase permeability. Dabigatran inhibited the formation of actin stress fibers induced by thrombin and inhibited consequent destabilization of junctional protein complexes and intercellular gap formation. The interaction of thrombin with protease activated receptor-1 activates the Rho A guanosine triphosphate (GTP)ase-myosin light chain (MLC) phosphorylation signaling axis, leading to actin cytoskeleton changes. This signaling pathway was effectively inhibited by dabigatran in endothelial cells. Consistently, the number of phosphorylated MLC-positive cells was significantly decreased in ischemic tissue of rat brains. These results indicate dabigatran blocks the ability of thrombin to induce vascular permeability and the resulting underlying signaling cascade in endothelial cells. Our findings provide evidence that dabigatran may confer a lower risk of intracerebral hemorrhage by preserving endothelial barrier integrity.
Full Text
https://www.sciencedirect.com/science/article/pii/S0049384818303244
DOI
10.1016/j.thromres.2018.04.019
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Neurology (신경과학교실) > 1. Journal Papers
Yonsei Authors
김영대(Kim, Young Dae) ORCID logo https://orcid.org/0000-0001-5750-2616
남효석(Nam, Hyo Suk) ORCID logo https://orcid.org/0000-0002-4415-3995
최현정(Choi, Hyun-Jung) ORCID logo https://orcid.org/0000-0003-3695-3420
허지회(Heo, Ji Hoe) ORCID logo https://orcid.org/0000-0001-9898-3321
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URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/163227
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