Vascular dysfunction in obese diabetic db/db mice involves the interplay between aldosterone/mineralocorticoid receptor and Rho kinase signaling

Abstract Activation of aldosterone/mineralocorticoid receptors (MR) has been implicated in vascular dysfunction of diabetes. Underlying mechanisms are elusive. Therefore, we investigated the role of Rho kinase (ROCK) in aldosterone/MR signaling and vascular dysfunction in a model of diabetes. Diabet...

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Autores principales:	Aurelie Nguyen Dinh Cat, Glaucia E. Callera, Malou Friederich-Persson, Ana Sanchez, Maria Gabriela Dulak-Lis, Sofia Tsiropoulou, Augusto C. Montezano, Ying He, Ana M. Briones, Frederic Jaisser, Rhian M. Touyz
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1cbc4ec98c8b49dfb0ee07f4993edd82
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spelling	oai:doaj.org-article:1cbc4ec98c8b49dfb0ee07f4993edd822021-12-02T15:08:23ZVascular dysfunction in obese diabetic db/db mice involves the interplay between aldosterone/mineralocorticoid receptor and Rho kinase signaling10.1038/s41598-018-21087-52045-2322https://doaj.org/article/1cbc4ec98c8b49dfb0ee07f4993edd822018-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-21087-5https://doaj.org/toc/2045-2322Abstract Activation of aldosterone/mineralocorticoid receptors (MR) has been implicated in vascular dysfunction of diabetes. Underlying mechanisms are elusive. Therefore, we investigated the role of Rho kinase (ROCK) in aldosterone/MR signaling and vascular dysfunction in a model of diabetes. Diabetic obese mice (db/db) and control counterparts (db/+) were treated with MR antagonist (MRA, potassium canrenoate, 30 mg/kg/day, 4 weeks) or ROCK inhibitor, fasudil (30 mg/kg/day, 3 weeks). Plasma aldosterone was increased in db/db versus db/+. This was associated with enhanced vascular MR signaling. Norepinephrine (NE)-induced contraction was increased in arteries from db/db mice. These responses were attenuated in mice treated with canrenoate or fasudil. Db/db mice displayed hypertrophic remodeling and increased arterial stiffness, improved by MR blockade. Vascular calcium sensitivity was similar between depolarized arteries from db/+ and db/db. Vascular hypercontractility in db/db mice was associated with increased myosin light chain phosphorylation and reduced expression of PKG-1α. Vascular RhoA/ROCK signaling and expression of pro-inflammatory and pro-fibrotic markers were exaggerated in db/db mice, effects that were attenuated by MRA. Fasudil, but not MRA, improved vascular insulin sensitivity in db/db mice, evidenced by normalization of Irs1 phosphorylation. Our data identify novel pathways involving MR-RhoA/ROCK-PKG-1 that underlie vascular dysfunction and injury in diabetic mice.Aurelie Nguyen Dinh CatGlaucia E. CalleraMalou Friederich-PerssonAna SanchezMaria Gabriela Dulak-LisSofia TsiropoulouAugusto C. MontezanoYing HeAna M. BrionesFrederic JaisserRhian M. TouyzNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-11 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Aurelie Nguyen Dinh Cat Glaucia E. Callera Malou Friederich-Persson Ana Sanchez Maria Gabriela Dulak-Lis Sofia Tsiropoulou Augusto C. Montezano Ying He Ana M. Briones Frederic Jaisser Rhian M. Touyz Vascular dysfunction in obese diabetic db/db mice involves the interplay between aldosterone/mineralocorticoid receptor and Rho kinase signaling
description	Abstract Activation of aldosterone/mineralocorticoid receptors (MR) has been implicated in vascular dysfunction of diabetes. Underlying mechanisms are elusive. Therefore, we investigated the role of Rho kinase (ROCK) in aldosterone/MR signaling and vascular dysfunction in a model of diabetes. Diabetic obese mice (db/db) and control counterparts (db/+) were treated with MR antagonist (MRA, potassium canrenoate, 30 mg/kg/day, 4 weeks) or ROCK inhibitor, fasudil (30 mg/kg/day, 3 weeks). Plasma aldosterone was increased in db/db versus db/+. This was associated with enhanced vascular MR signaling. Norepinephrine (NE)-induced contraction was increased in arteries from db/db mice. These responses were attenuated in mice treated with canrenoate or fasudil. Db/db mice displayed hypertrophic remodeling and increased arterial stiffness, improved by MR blockade. Vascular calcium sensitivity was similar between depolarized arteries from db/+ and db/db. Vascular hypercontractility in db/db mice was associated with increased myosin light chain phosphorylation and reduced expression of PKG-1α. Vascular RhoA/ROCK signaling and expression of pro-inflammatory and pro-fibrotic markers were exaggerated in db/db mice, effects that were attenuated by MRA. Fasudil, but not MRA, improved vascular insulin sensitivity in db/db mice, evidenced by normalization of Irs1 phosphorylation. Our data identify novel pathways involving MR-RhoA/ROCK-PKG-1 that underlie vascular dysfunction and injury in diabetic mice.
format	article
author	Aurelie Nguyen Dinh Cat Glaucia E. Callera Malou Friederich-Persson Ana Sanchez Maria Gabriela Dulak-Lis Sofia Tsiropoulou Augusto C. Montezano Ying He Ana M. Briones Frederic Jaisser Rhian M. Touyz
author_facet	Aurelie Nguyen Dinh Cat Glaucia E. Callera Malou Friederich-Persson Ana Sanchez Maria Gabriela Dulak-Lis Sofia Tsiropoulou Augusto C. Montezano Ying He Ana M. Briones Frederic Jaisser Rhian M. Touyz
author_sort	Aurelie Nguyen Dinh Cat
title	Vascular dysfunction in obese diabetic db/db mice involves the interplay between aldosterone/mineralocorticoid receptor and Rho kinase signaling
title_short	Vascular dysfunction in obese diabetic db/db mice involves the interplay between aldosterone/mineralocorticoid receptor and Rho kinase signaling
title_full	Vascular dysfunction in obese diabetic db/db mice involves the interplay between aldosterone/mineralocorticoid receptor and Rho kinase signaling
title_fullStr	Vascular dysfunction in obese diabetic db/db mice involves the interplay between aldosterone/mineralocorticoid receptor and Rho kinase signaling
title_full_unstemmed	Vascular dysfunction in obese diabetic db/db mice involves the interplay between aldosterone/mineralocorticoid receptor and Rho kinase signaling
title_sort	vascular dysfunction in obese diabetic db/db mice involves the interplay between aldosterone/mineralocorticoid receptor and rho kinase signaling
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/1cbc4ec98c8b49dfb0ee07f4993edd82
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Vascular dysfunction in obese diabetic db/db mice involves the interplay between aldosterone/mineralocorticoid receptor and Rho kinase signaling

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