Rahadian, Arief and Fukuda, Daiju and Salim, Hotimah Masdan and Yagi, Shusuke and Kusunose, Kenya and Yamada, Hirotsugu and Soeki, Takeshi and Shimabukuro, Michio and Sata, Masataka (2020) Thrombin inhibition by dabigatran attenuates endothelial dysfunction in diabetic mice. Vascular Pharmacology, 124. pp. 1-8. ISSN 1537-1891
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Abstract
Diabetic patients have coagulation abnormalities, in which thrombin plays a key role. Whereas accumulating evidence suggests that it also contributes to the development of vascular dysfunction through the activation of protease-activated receptors (PARs). Here we investigated whether the blockade of thrombin attenuates endothelial dysfunction in diabetic mice. Induction of diabetes by streptozotocin (STZ) increased the expression of PAR1, PAR3, and PAR4 in the aorta. STZ-induced diabetic mice showed impairment of endothelial function, while the administration of dabigatran etexilate, a direct thrombin inhibitor, significantly attenuated endothelial dysfunction in diabetic mice with no alteration of metabolic parameters including blood glucose level. Dabigatran did not affect endothelium-independent vasodilation. Dabigatran decreased the expression of inflammatory molecules (e.g., MCP-1 and ICAM-1) in the aorta of diabetic mice. Thrombin increased the expression of these inflammatory molecules and the phosphorylation of IκBα, and decreased the phosphorylation of eNOSSer1177 in human umbilical endothelial cells (HUVEC). Thrombin significantly impaired the endothelium-dependent vascular response of aortic rings obtained from wild-type mice. Inhibition of NF-κB attenuated thrombin-induced inflammatory molecule expression in HUVEC and ameliorated thrombin-induced endothelial dysfunction in aortic rings. Dabigatran attenuated the development of diabetes-induced endothelial dysfunction. Thrombin signaling may serve as a potential therapeutic target in diabetic condition.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Dabigatran; Diabetes; Endothelial function; Inflammation; Thrombin |
| Subjects: | R Medicine > R Medicine (General) |
| Divisions: | Faculty of Medicine > Program Study of Medicine |
| Depositing User: | Mr. . Aji |
| Date Deposited: | 13 Dec 2022 02:59 |
| Last Modified: | 13 Dec 2022 02:59 |
| URI: | http://repository.unusa.ac.id/id/eprint/9105 |
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