Adipocyte-specific mineralocorticoid receptor overexpression in mice is associated with metabolic syndrome and vascular dysfunction: role of redox-sensitive PKG-1 and Rho kinase

Nguyen Dinh Cat, A. et al. (2016) Adipocyte-specific mineralocorticoid receptor overexpression in mice is associated with metabolic syndrome and vascular dysfunction: role of redox-sensitive PKG-1 and Rho kinase. Diabetes, 65(8), pp. 2392-2403. (doi:10.2337/db15-1627) (PMID:27207514)

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Abstract

Mineralocorticoid receptor (MR) expression is increased in adipose tissue from obese individuals and animals. We previously demonstrated that adipocyte-MR overexpression (Adipo-MROE) in mice is associated with metabolic changes. Whether adipocyte MR directly influences vascular function in these mice is unknown. We tested this hypothesis in resistant mesenteric arteries from Adipo-MROE mice using myography and in cultured adipocytes. Molecular mechanisms were probed in vessels/vascular smooth muscle cells and adipose tissue/adipocytes and focused on redox-sensitive pathways, Rho kinase activity, and protein kinase G type-1 (PKG-1) signaling. Adipo-MROE versus control-MR mice exhibited reduced vascular contractility, associated with increased generation of adipocyte-derived hydrogen peroxide, activation of vascular redox-sensitive PKG-1, and downregulation of Rho kinase activity. Associated with these vascular changes was increased elastin content in Adipo-MROE. Inhibition of PKG-1 with Rp-8-Br-PET-cGMPS normalized vascular contractility in Adipo-MROE. In the presence of adipocyte-conditioned culture medium, anticontractile effects of the adipose tissue were lost in Adipo-MROE mice but not in control-MR mice. In conclusion, adipocyte-MR upregulation leads to impaired contractility with preserved endothelial function and normal blood pressure. Increased elasticity may contribute to hypocontractility. We also identify functional cross talk between adipocyte MR and arteries and describe novel mechanisms involving redox-sensitive PKG-1 and Rho kinase. Our results suggest that adipose tissue from Adipo-MROE secrete vasoactive factors that preferentially influence vascular smooth muscle cells rather than endothelial cells. Our findings may be important in obesity/adiposity where adipocyte-MR expression/signaling is amplified and vascular risk increased.

Item Type:Articles
Additional Information:This work was supported by grants from the British Heart Foundation (RG/13/7/30099, CH/12/429762) and the Canadian Institutes of Health Research (CIHR 44018). A.N.D.C. held a postdoctoral fellowship from the CIHR. F.J. was supported through INSERM and Fondation de France (2014-00047968). R.M.T. was supported through a Canada Research Chair/Canadian Foundation for Innovation award and a British Heart Foundation Chair. R.M.T. and F.J. benefited from support of the European COST-ADMIRE 1301 network.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Tsiropoulou, Miss Sofia and Dulak-Lis, Ms Maria and Sanchez, Dr Ana and Anagnostopoulou, Dr Aikaterini and Montezano, Dr Augusto and Nguyen Dinh Cat, Dr Aurelie and Touyz, Professor Rhian
Authors: Nguyen Dinh Cat, A., Antunes, T. T., Callera, G. E., Sanchez, A., Tsiropoulou, S., Dulak-Lis, M., Anagnostopoulou, A., He, Y., Montezano, A., Jaisser, F., and Touyz, R. M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Diabetes
Publisher:American Diabetes Association
ISSN:0012-1797
ISSN (Online):1939-327X

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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