title: Endothelial mineralocorticoid receptor activation mediates endothelial dysfunction in diet-induced obesity.
abstract: OBJECTIVE
  Aldosterone plays a crucial role in cardiovascular disease. 'Systemic' inhibition of its mineralocorticoid receptor (MR) decreases atherosclerosis by reducing inflammation and oxidative stress. Obesity, an important cardiovascular risk factor, is an inflammatory disease associated with increased plasma aldosterone levels. We have investigated the role of the 'endothelial' MR in obesity-induced endothelial dysfunction, the earliest stage in atherogenesis.
  
  
  RESULTS
  C57BL/6 mice were exposed to a normal chow diet (ND) or a high-fat diet (HFD) alone or in combination with the MR antagonist eplerenone (200 mg/kg/day) for 14 weeks. Diet-induced obesity impaired endothelium-dependent relaxation in response to acetylcholine, whereas eplerenone treatment of obese mice prevented this. Expression analyses in aortic endothelial cells isolated from these mice revealed that eplerenone attenuated expression of pro-oxidative NADPH oxidase (subunits p22phox, p40phox) and increased expression of antioxidative genes (glutathione peroxidase-1, superoxide dismutase-1 and -3) in obesity. Eplerenone did not affect obesity-induced upregulation of cyclooxygenase (COX)-1 or prostacyclin synthase. Endothelial-specific MR deletion prevented endothelial dysfunction in obese (exhibiting high 'endogenous' aldosterone) and in 'exogenous' aldosterone-infused lean mice. Pre-incubation of aortic rings from aldosterone-treated animals with the COX-inhibitor indomethacin restored endothelial function. Exogenous aldosterone administration induced endothelial expression of p22phox in the presence, but not in the absence of the endothelial MR.
  
  
  CONCLUSIONS
  Obesity-induced endothelial dysfunction depends on the 'endothelial' MR and is mediated by an imbalance of oxidative stress-modulating mechanisms. Therefore, MR antagonists may represent an attractive therapeutic strategy in the increasing population of obese patients to decrease vascular dysfunction and subsequent atherosclerotic complications.
authors.affiliation: Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
authors.forename: Nicola
authors.initials: N
authors.lastname: Schäfer
authors.forename: Christine
authors.initials: C
authors.lastname: Lohmann
authors.forename: Stephan
authors.initials: S
authors.lastname: Winnik
authors.forename: Lambertus J
authors.initials: LJ
authors.lastname: van Tits
authors.forename: Melroy X
authors.initials: MX
authors.lastname: Miranda
authors.forename: Athanasios
authors.initials: A
authors.lastname: Vergopoulos
authors.forename: Frank
authors.initials: F
authors.lastname: Ruschitzka
authors.forename: Jürg
authors.initials: J
authors.lastname: Nussberger
authors.forename: Stefan
authors.initials: S
authors.lastname: Berger
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lüscher
authors.forename: François
authors.initials: F
authors.lastname: Verrey
authors.forename: Christian M
authors.initials: CM
authors.lastname: Matter
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects; D000450:Aldosterone / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001011:Aorta / Q000187:drug effects; D051545:Cyclooxygenase 1 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects*; D004730:Endothelium, Vascular / Q000187:drug effects*; D000077545:Eplerenone; D005979:Glutathione Peroxidase / Q000378:metabolism; D006943:Hyperglycemia / Q000188:drug therapy; D007249:Inflammation / Q000188:drug therapy; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D009765:Obesity / Q000209:etiology* / Q000503:physiopathology; D018384:Oxidative Stress / Q000187:drug effects; D018161:Receptors, Mineralocorticoid / Q000502:physiology*; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D015854:Up-Regulation; D000094765:Glutathione Peroxidase GPX1
chemical_list: D000975:Antioxidants; D016861:Cyclooxygenase Inhibitors; D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D000450:Aldosterone; D000077545:Eplerenone; D003577:Cytochrome P-450 Enzyme System; D005979:Glutathione Peroxidase; D051545:Cyclooxygenase 1; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse
keywords: Aldosterone; Endothelial; Mineralocorticoid receptor; Obesity