| Title: |
Thrombin inhibition prevents endothelial dysfunction and reverses 20-hete overproduction without affecting blood pressure in angiotensin ii-induced hypertension in mice |
| Authors: |
Kij, Agnieszka; Bar, Anna; Przyborowski, Kamil; Proniewski, Bartosz; Mateuszuk, Lukasz; Jasztal, Agnieszka; Kieronska-Rudek, Anna; Marczyk, Brygida; Matyjaszczyk-Gwarda, Karolina; Tworzydlo, Anna; Enggaard, Camilla; Hansen, Pernille B.Lærkegaard; Jensen, Boye; Walczak, Maria; Chlopicki, Stefan |
| Source: |
Kij, A, Bar, A, Przyborowski, K, Proniewski, B, Mateuszuk, L, Jasztal, A, Kieronska-Rudek, A, Marczyk, B, Matyjaszczyk-Gwarda, K, Tworzydlo, A, Enggaard, C, Hansen, P B L, Jensen, B, Walczak, M & Chlopicki, S 2021, 'Thrombin inhibition prevents endothelial dysfunction and reverses 20-hete overproduction without affecting blood pressure in angiotensin ii-induced hypertension in mice', International Journal of Molecular Sciences, vol. 22, no. 16, 8664. https://doi.org/10.3390/ijms22168664 |
| Publication Year: |
2021 |
| Collection: |
University of Southern Denmark: Research Output / Syddansk Universitet |
| Subject Terms: |
20-HETE; Angiotensin II; Dabigatran; Endothelial function; MRI; Nitric oxide; NO; Thrombin activ-ity; Intercellular Adhesion Molecule-1/metabolism; Male; Hypertension/blood; Nitric Oxide/metabolism; Tandem Mass Spectrometry; Animals; Dabigatran/administration & dosage; Chromatography; Liquid; Vascular Remodeling/drug effects; von Willebrand Factor/metabolism; Mice; Antithrombins/administration & dosage; Angiotensin II/adverse effects; Disease Models; Animal; Hydroxyeicosatetraenoic Acids/blood |
| Description: |
Angiotensin II (Ang II) induces hypertension and endothelial dysfunction, but the involvement of thrombin in these responses is not clear. Here, we assessed the effects of the inhibition of thrombin activity by dabigatran on Ang II-induced hypertension and endothelial dysfunction in mice with a particular focus on NO- and 20-HETE-dependent pathways. As expected, dabigatran administration significantly delayed thrombin generation (CAT assay) in Ang II-treated hypertensive mice, and interestingly, it prevented endothelial dysfunction development, but it did not affect elevated blood pressure nor excessive aortic wall thickening. Dabigatran’s effects on endothelial function in Ang II-treated mice were evidenced by improved NO-dependent relaxation in the aorta in response to acetylcholine in vivo (MRI measurements) and increased systemic NO bioavailability (NO2− quantification) with a concomitant increased ex vivo production of endothelium-derived NO (EPR analysis). Dabigatran treatment also contributed to the reduction in the endothelial expression of pro-inflammatory vWF and ICAM-1. Interestingly, the fall in systemic NO bioavailability in Ang II-treated mice was associated with increased 20-HETE concentration in plasma (UPLC-MS/MS analysis), which was normalised by dabigatran treatment. Taking together, the inhibition of thrombin activity in Ang II-induced hypertension in mice improves the NO-dependent function of vascular endothelium and normalises the 20-HETE-depedent pathway without affecting the blood pressure and vascular remodelling. ; Angiotensin II (Ang II) induces hypertension and endothelial dysfunction, but the involvement of thrombin in these responses is not clear. Here, we assessed the effects of the inhibition of thrombin activity by dabigatran on Ang II-induced hypertension and endothelial dysfunction in mice with a particular focus on NO-and 20-HETE-dependent pathways. As expected, dabigatran administration significantly delayed thrombin generation (CAT assay) in Ang II-treated hypertensive mice, ... |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| ISSN: |
1422-0067 |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/34445374; info:eu-repo/semantics/altIdentifier/pissn/1422-0067 |
| DOI: |
10.3390/ijms22168664 |
| Availability: |
https://portal.findresearcher.sdu.dk/da/publications/e805c384-480d-429e-b076-0d2f473bc365; https://doi.org/10.3390/ijms22168664; https://findresearcher.sdu.dk/ws/files/191272186/Open_Access_Version.pdf |
| Rights: |
info:eu-repo/semantics/openAccess ; http://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.D1676A48 |
| Database: |
BASE |