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.
Bibliographical noteFunding Information:
This research was supported by a grant from the Korea Healthcare Technology R&D Project, Ministry of Health and Welfare, Republic of Korea ( HI08C2149 ), by a faculty research grant from Yonsei University College of Medicine ( 2016-32-0063 ; 2017-32-0101 ), and by a Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education ( 2015R1D1A1A01056703 ). This work was also supported in part by the Brain Korea (BK21) PLUS program.
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