Thrombin Inhibition Prevents Endothelial Dysfunction and Reverses 20-HETE Overproduction without Affecting Blood Pressure in Angiotensin II-Induced Hypertension in Mice
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 part...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-08-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/16/8664 |
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| author | Agnieszka Kij Anna Bar Kamil Przyborowski Bartosz Proniewski Lukasz Mateuszuk Agnieszka Jasztal Anna Kieronska-Rudek Brygida Marczyk Karolina Matyjaszczyk-Gwarda Anna Tworzydlo Camilla Enggaard Pernille B. Lærkegaard Hansen Boye Jensen Maria Walczak Stefan Chlopicki |
| author_facet | Agnieszka Kij Anna Bar Kamil Przyborowski Bartosz Proniewski Lukasz Mateuszuk Agnieszka Jasztal Anna Kieronska-Rudek Brygida Marczyk Karolina Matyjaszczyk-Gwarda Anna Tworzydlo Camilla Enggaard Pernille B. Lærkegaard Hansen Boye Jensen Maria Walczak Stefan Chlopicki |
| author_sort | Agnieszka Kij |
| collection | DOAJ |
| 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 (NO<sub>2</sub><sup>−</sup> 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. |
| first_indexed | 2024-03-10T08:44:50Z |
| format | Article |
| id | doaj.art-74f4163fb2c84bbba8e55ba2f71cae96 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T08:44:50Z |
| publishDate | 2021-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-74f4163fb2c84bbba8e55ba2f71cae962023-11-22T07:58:40ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-08-012216866410.3390/ijms22168664Thrombin Inhibition Prevents Endothelial Dysfunction and Reverses 20-HETE Overproduction without Affecting Blood Pressure in Angiotensin II-Induced Hypertension in MiceAgnieszka Kij0Anna Bar1Kamil Przyborowski2Bartosz Proniewski3Lukasz Mateuszuk4Agnieszka Jasztal5Anna Kieronska-Rudek6Brygida Marczyk7Karolina Matyjaszczyk-Gwarda8Anna Tworzydlo9Camilla Enggaard10Pernille B. Lærkegaard Hansen11Boye Jensen12Maria Walczak13Stefan Chlopicki14Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, PolandJagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, PolandJagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, PolandJagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, PolandJagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, PolandJagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, PolandJagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, PolandJagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, PolandJagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, PolandJagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, PolandDepartment of Cardiovascular and Renal Research, University of Southern Denmark, J.B. Winsløws Vej 21, 5000 Odense, DenmarkDepartment of Cardiovascular and Renal Research, University of Southern Denmark, J.B. Winsløws Vej 21, 5000 Odense, DenmarkDepartment of Cardiovascular and Renal Research, University of Southern Denmark, J.B. Winsløws Vej 21, 5000 Odense, DenmarkJagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, PolandJagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, PolandAngiotensin 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 (NO<sub>2</sub><sup>−</sup> 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.https://www.mdpi.com/1422-0067/22/16/866420-HETEangiotensin IIendothelial functionMRInitric oxideNO |
| spellingShingle | Agnieszka Kij Anna Bar Kamil Przyborowski Bartosz Proniewski Lukasz Mateuszuk Agnieszka Jasztal Anna Kieronska-Rudek Brygida Marczyk Karolina Matyjaszczyk-Gwarda Anna Tworzydlo Camilla Enggaard Pernille B. Lærkegaard Hansen Boye Jensen Maria Walczak Stefan Chlopicki 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 20-HETE angiotensin II endothelial function MRI nitric oxide NO |
| title | Thrombin Inhibition Prevents Endothelial Dysfunction and Reverses 20-HETE Overproduction without Affecting Blood Pressure in Angiotensin II-Induced Hypertension in Mice |
| title_full | Thrombin Inhibition Prevents Endothelial Dysfunction and Reverses 20-HETE Overproduction without Affecting Blood Pressure in Angiotensin II-Induced Hypertension in Mice |
| title_fullStr | Thrombin Inhibition Prevents Endothelial Dysfunction and Reverses 20-HETE Overproduction without Affecting Blood Pressure in Angiotensin II-Induced Hypertension in Mice |
| title_full_unstemmed | Thrombin Inhibition Prevents Endothelial Dysfunction and Reverses 20-HETE Overproduction without Affecting Blood Pressure in Angiotensin II-Induced Hypertension in Mice |
| title_short | Thrombin Inhibition Prevents Endothelial Dysfunction and Reverses 20-HETE Overproduction without Affecting Blood Pressure in Angiotensin II-Induced Hypertension in Mice |
| title_sort | thrombin inhibition prevents endothelial dysfunction and reverses 20 hete overproduction without affecting blood pressure in angiotensin ii induced hypertension in mice |
| topic | 20-HETE angiotensin II endothelial function MRI nitric oxide NO |
| url | https://www.mdpi.com/1422-0067/22/16/8664 |
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