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A Selective Mineralocorticoid Receptor Blocker, Esaxerenone, Attenuates Vascular Dysfunction in Diabetic C57BL/6 Mice
Aims: Pharmacological blockade of mineralocorticoid receptors (MRs) is a potential therapeutic approach to reduce cardiovascular complications since MRs play a crucial role in cardiovascular regulation. Recent studies suggest that MR antagonists affect several extrarenal tissues, including vessel fu...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Japan Atherosclerosis Society
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10067342/ https://www.ncbi.nlm.nih.gov/pubmed/35732424 http://dx.doi.org/10.5551/jat.63382 |
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author | Munkhjargal, Uugantsetseg Fukuda, Daiju Ganbaatar, Byambasuren Suto, Kumiko Matsuura, Tomomi Ise, Takayuki Kusunose, Kenya Yamaguchi, Koji Yagi, Shusuke Yamada, Hirotsugu Soeki, Takeshi Wakatsuki, Tetsuzo Sata, Masataka |
author_facet | Munkhjargal, Uugantsetseg Fukuda, Daiju Ganbaatar, Byambasuren Suto, Kumiko Matsuura, Tomomi Ise, Takayuki Kusunose, Kenya Yamaguchi, Koji Yagi, Shusuke Yamada, Hirotsugu Soeki, Takeshi Wakatsuki, Tetsuzo Sata, Masataka |
author_sort | Munkhjargal, Uugantsetseg |
collection | PubMed |
description | Aims: Pharmacological blockade of mineralocorticoid receptors (MRs) is a potential therapeutic approach to reduce cardiovascular complications since MRs play a crucial role in cardiovascular regulation. Recent studies suggest that MR antagonists affect several extrarenal tissues, including vessel function. We investigated the effect of a novel nonsteroidal selective MR blocker, esaxerenone, on diabetes-induced vascular dysfunction. Methods: Diabetes was induced by a single dose of streptozotocin in 8-week-old male C57BL/6 mice. Esaxerenone (3 mg/kg/day) or a vehicle was administered by gavage to diabetic mice for 3 weeks. Metabolic parameters, plasma aldosterone levels, and parameters related to renal function were measured. Endothelium-dependent or -independent vascular responses of the aortic segments were analyzed with acetylcholine or sodium nitroprusside, respectively. Human umbilical vein endothelial cells (HUVECs) were used for the in vitro study. Results: Induction of diabetes elevated plasma aldosterone level (P<0.05) and impaired endothelium-dependent vascular relaxation (P<0.05). The administration of esaxerenone ameliorated the endothelial dysfunction (P<0.01) without the alteration of metabolic parameters, blood pressure, and renal function. Esaxerenone improved the eNOS(Ser1177) phosphorylation in the aorta obtained from diabetic mice (P<0.05) compared with that in the vehicle-treated group. Furthermore, a major MR agonist, aldosterone, decreased eNOS(Ser1177) phosphorylation and increased eNOS(Thr495) phosphorylation in HUVECs, which recovered with esaxerenone. Esaxerenone ameliorated the endothelium-dependent vascular relaxation caused by aldosterone in the aortic segments obtained from C57BL/6 mice (P<0.001). Conclusion: Esaxerenone attenuates the development of diabetes-induced endothelial dysfunction in mice. These results suggest that esaxerenone has potential vascular protective effects in individuals with diabetes. |
format | Online Article Text |
id | pubmed-10067342 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Japan Atherosclerosis Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-100673422023-04-04 A Selective Mineralocorticoid Receptor Blocker, Esaxerenone, Attenuates Vascular Dysfunction in Diabetic C57BL/6 Mice Munkhjargal, Uugantsetseg Fukuda, Daiju Ganbaatar, Byambasuren Suto, Kumiko Matsuura, Tomomi Ise, Takayuki Kusunose, Kenya Yamaguchi, Koji Yagi, Shusuke Yamada, Hirotsugu Soeki, Takeshi Wakatsuki, Tetsuzo Sata, Masataka J Atheroscler Thromb Original Article Aims: Pharmacological blockade of mineralocorticoid receptors (MRs) is a potential therapeutic approach to reduce cardiovascular complications since MRs play a crucial role in cardiovascular regulation. Recent studies suggest that MR antagonists affect several extrarenal tissues, including vessel function. We investigated the effect of a novel nonsteroidal selective MR blocker, esaxerenone, on diabetes-induced vascular dysfunction. Methods: Diabetes was induced by a single dose of streptozotocin in 8-week-old male C57BL/6 mice. Esaxerenone (3 mg/kg/day) or a vehicle was administered by gavage to diabetic mice for 3 weeks. Metabolic parameters, plasma aldosterone levels, and parameters related to renal function were measured. Endothelium-dependent or -independent vascular responses of the aortic segments were analyzed with acetylcholine or sodium nitroprusside, respectively. Human umbilical vein endothelial cells (HUVECs) were used for the in vitro study. Results: Induction of diabetes elevated plasma aldosterone level (P<0.05) and impaired endothelium-dependent vascular relaxation (P<0.05). The administration of esaxerenone ameliorated the endothelial dysfunction (P<0.01) without the alteration of metabolic parameters, blood pressure, and renal function. Esaxerenone improved the eNOS(Ser1177) phosphorylation in the aorta obtained from diabetic mice (P<0.05) compared with that in the vehicle-treated group. Furthermore, a major MR agonist, aldosterone, decreased eNOS(Ser1177) phosphorylation and increased eNOS(Thr495) phosphorylation in HUVECs, which recovered with esaxerenone. Esaxerenone ameliorated the endothelium-dependent vascular relaxation caused by aldosterone in the aortic segments obtained from C57BL/6 mice (P<0.001). Conclusion: Esaxerenone attenuates the development of diabetes-induced endothelial dysfunction in mice. These results suggest that esaxerenone has potential vascular protective effects in individuals with diabetes. Japan Atherosclerosis Society 2023-04-01 2022-06-23 /pmc/articles/PMC10067342/ /pubmed/35732424 http://dx.doi.org/10.5551/jat.63382 Text en 2023 Japan Atherosclerosis Society https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License.http://creativecommons.org/licenses/by-nc-sa/4.0/ (https://creativecommons.org/licenses/by-nc-sa/4.0/) |
spellingShingle | Original Article Munkhjargal, Uugantsetseg Fukuda, Daiju Ganbaatar, Byambasuren Suto, Kumiko Matsuura, Tomomi Ise, Takayuki Kusunose, Kenya Yamaguchi, Koji Yagi, Shusuke Yamada, Hirotsugu Soeki, Takeshi Wakatsuki, Tetsuzo Sata, Masataka A Selective Mineralocorticoid Receptor Blocker, Esaxerenone, Attenuates Vascular Dysfunction in Diabetic C57BL/6 Mice |
title | A Selective Mineralocorticoid Receptor Blocker, Esaxerenone, Attenuates Vascular Dysfunction in Diabetic C57BL/6 Mice |
title_full | A Selective Mineralocorticoid Receptor Blocker, Esaxerenone, Attenuates Vascular Dysfunction in Diabetic C57BL/6 Mice |
title_fullStr | A Selective Mineralocorticoid Receptor Blocker, Esaxerenone, Attenuates Vascular Dysfunction in Diabetic C57BL/6 Mice |
title_full_unstemmed | A Selective Mineralocorticoid Receptor Blocker, Esaxerenone, Attenuates Vascular Dysfunction in Diabetic C57BL/6 Mice |
title_short | A Selective Mineralocorticoid Receptor Blocker, Esaxerenone, Attenuates Vascular Dysfunction in Diabetic C57BL/6 Mice |
title_sort | selective mineralocorticoid receptor blocker, esaxerenone, attenuates vascular dysfunction in diabetic c57bl/6 mice |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10067342/ https://www.ncbi.nlm.nih.gov/pubmed/35732424 http://dx.doi.org/10.5551/jat.63382 |
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