Mineralocorticoid Receptor and Rhoa/rho Kinase Contribute to Vascular Dysfunction in Obese Db/db Mice

Nguyen Dinh Cat, A., Callera, G. E., Antunes, T. T., He, Y., Montezano, A. C., Bruder-Nascimento, T. and Touyz, R. M. (2013) Mineralocorticoid Receptor and Rhoa/rho Kinase Contribute to Vascular Dysfunction in Obese Db/db Mice. Hypertension, 62(3 Sup), A373.

Abstract

Increasing evidence indicates that adipose tissue modulates vascular function. Our previous studies demonstrated that adipocytes secrete aldosterone. We hypothesized that adipocyte-releasing factors induce vascular dysfunction through mineralocorticoid receptor (MR)-dependent mechanisms. This study explored the small G protein RhoA/Rho kinase as a pathway linking aldosterone/MR and the paracrine effects of adipose tissue in the vasculature, since the activation of this pathway regulates vascular contraction. Diabetic obese mice (db/db) and their control counterparts (db/+) were treated with MR antagonist (MRA) (K canrenoate, 30mg/Kg/day, S.C., 4 weeks) or RhoA/Rho kinase inhibitor, fasudil (30 mg/Kg/day, S.C., 3 weeks). Blood pressure levels were similar between groups. Fasudil, but not MRA, reduced plasma glucose levels in db/db mice (db/+:12.3±6; db/db: 30.1±3; MRA-treated db/db: 32.5±2; fasudil treated db/db: 17.1±2; mmoL/mL). Arteries from db/db mice displayed reduced relaxation to 10-5M acetycholine (Ach; db/+:79.4±3.9% vs db/db: 14.3±3.1%). Arteries from MRA-treated db/db mice exposed to fat conditioned medium (FCM) had improved responses to Ach (MRA-treated db/db: 28.3±1.9% vs MRA-treated db/db +FCM: 42.8±4.3%). Increased norepinephrine (NE)-induced contraction was observed in db/db mice in endothelium-denuded arteries (10-5M NE; db/+: 1.5 ± 0.1 vs db/db: 2.2 ± 0.1; mN/mm). NE responses were reduced in MRA-treated db/db mice (1.7±0.1 mN/mm) or fasudil (1.6±0.2 mN/mm). Vascular calcium sensitivity was similar between depolarized arteries from db/+ and db/db. Fasudil treatment reduced calcium-induced contraction in both groups with greater effect in db/db mice (5 mmol/L CaCl2; db/+: 73 % vs db/db: 57 %). MR blockade did not affect vascular RhoA/Rho kinase activity (RhoA membrane to cytosol translocation) in db/db mice. Our data suggest that in db/db mice: MR and RhoA/Rho kinase signaling contribute to adipose modulation of vascular/contraction. While MR plays a role in vascular relaxation, RhoA/Rho kinase signalling is important in contractile dysfunction, adipocyte secretion, and glucose metabolism - processes that may contribute to cardiovascular injury in obesity-associated diabetes.

• Item Type: Articles
• Additional Information: American-Heart-Association High Blood Pressure Research Scientific Sessions, New Orleans, LA, USA, 11-14 Sept 2013.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Montezano, Dr Augusto and Nguyen Dinh Cat, Dr Aurelie and Touyz, Professor Rhian
• Authors: Nguyen Dinh Cat, A., Callera, G. E., Antunes, T. T., He, Y., Montezano, A. C., Bruder-Nascimento, T., and Touyz, R. M.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Hypertension
• Publisher: American Heart Association
• ISSN: 0194-911X
• ISSN (Online): 1524-4563