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Vascular dysfunction in obese diabetic db/db mice involves the interplay between aldosterone/mineralocorticoid receptor and Rho kinase signaling
Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland..
Univ Ottawa, Ottawa Hosp, Res Inst, Kidney Res Ctr, Ottawa, ON, Canada..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland.
Univ Complutense, Fac Farm, Dept Fisiol, Madrid, Spain..
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2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 2952Article in journal (Refereed) Published
Abstract [en]

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-1 alpha. 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.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2018. Vol. 8, article id 2952
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Endocrinology and Diabetes
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URN: urn:nbn:se:uu:diva-348111DOI: 10.1038/s41598-018-21087-5ISI: 000424871500019OAI: oai:DiVA.org:uu-348111DiVA, id: diva2:1196780
Available from: 2018-04-11 Created: 2018-04-11 Last updated: 2018-04-11Bibliographically approved

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Friederich, Malou

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