title: Adipocyte-Specific Mineralocorticoid Receptor Overexpression in Mice Is Associated With Metabolic Syndrome and Vascular Dysfunction: Role of Redox-Sensitive PKG-1 and Rho Kinase.
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.
authors.affiliation: Cardiovascular Research and Medical Sciences Institute, University of Glasgow, Glasgow, U.K. cattuong.ndc@gmail.com rhian.touyz@glasgow.ac.uk.
authors.forename: Aurelie
authors.initials: A
authors.lastname: Nguyen Dinh Cat
authors.affiliation: Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Tayze T
authors.initials: TT
authors.lastname: Antunes
authors.affiliation: Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Glaucia E
authors.initials: GE
authors.lastname: Callera
authors.affiliation: Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense, Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Sanchez
authors.affiliation: Cardiovascular Research and Medical Sciences Institute, University of Glasgow, Glasgow, U.K.
authors.forename: Sofia
authors.initials: S
authors.lastname: Tsiropoulou
authors.affiliation: Cardiovascular Research and Medical Sciences Institute, University of Glasgow, Glasgow, U.K.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Dulak-Lis
authors.affiliation: Cardiovascular Research and Medical Sciences Institute, University of Glasgow, Glasgow, U.K.
authors.forename: Aikaterini
authors.initials: A
authors.lastname: Anagnostopoulou
authors.affiliation: Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Ying
authors.initials: Y
authors.lastname: He
authors.affiliation: Cardiovascular Research and Medical Sciences Institute, University of Glasgow, Glasgow, U.K.
authors.forename: Augusto C
authors.initials: AC
authors.lastname: Montezano
authors.affiliation: INSERM Unit 1138 Team 1, Centre de Recherche des Cordeliers, University Pierre and Marie Curie, Paris, France INSERM, Clinical Investigation Centre 1430, APHP, Henri Mondor Hospital, Pole VERDI, Paris East University, Creteil, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Jaisser
authors.affiliation: Cardiovascular Research and Medical Sciences Institute, University of Glasgow, Glasgow, U.K. Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada cattuong.ndc@gmail.com rhian.touyz@glasgow.ac.uk.
authors.forename: Rhian M
authors.initials: RM
authors.lastname: Touyz
mesh_terms: D017667:Adipocytes / Q000378:metabolism*; D000450:Aldosterone / Q000097:blood; D000804:Angiotensin II / Q000097:blood; D000818:Animals; D002478:Cells, Cultured; D003345:Corticosterone / Q000097:blood; D017077:Culture Media, Conditioned; D004549:Elastin / Q000378:metabolism; D006801:Humans; D050152:Intra-Abdominal Fat / Q000378:metabolism; D008297:Male; D024821:Metabolic Syndrome / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D010084:Oxidation-Reduction; D010766:Phosphorylation; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D017077:Culture Media, Conditioned; D018161:Receptors, Mineralocorticoid; D000804:Angiotensin II; D000450:Aldosterone; D004549:Elastin; D054460:rho-Associated Kinases; D003345:Corticosterone