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

Nguyen Dinh Cat, A. et al. (2018) Vascular dysfunction in obese diabetic db/db mice involves the interplay between aldosterone/mineralocorticoid receptor and Rho kinase signaling. Scientific Reports, 8, 2952. (doi: 10.1038/s41598-018-21087-5) (PMID:29440699) (PMCID:PMC5811612)

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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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Briones, Dr Ana and Tsiropoulou, Miss Sofia and Dulak-Lis, Ms Maria and Sanchez, Dr Ana and Friederich-Persson, Dr Malou and Montezano, Dr Augusto and Nguyen Dinh Cat, Dr Aurelie and Touyz, Professor Rhian
Authors: Nguyen Dinh Cat, A., Callera, G. E., Friederich-Persson, M., Sanchez, A., Dulak-Lis, M. G., Tsiropoulou, S., Montezano, A. C., He, Y., Briones, A. M., Jaisser, F., and Touyz, R. M.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Journal Name:Scientific Reports
Publisher:Nature Research
ISSN (Online):2045-2322
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in Scientific Reports 8: 2952
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
607382Vascular Noxs as therapeutic targets and biomarkers in hypertensionRhian TouyzBritish Heart Foundation (BHF)RG/13/7/30099RI CARDIOVASCULAR & MEDICAL SCIENCES