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Endothelial mineralocorticoid receptor activation mediates endothelial dysfunction in diet-induced obesity

Schäfer, Nicola ; Lohmann, Christine ; Winnik, Stephan ; van Tits, Lambertus J. ; Miranda, Melroy X. ; Vergopoulos, Athanasios ; Ruschitzka, Frank ; Nussberger, Jürg ; Berger, Stefan ; Lüscher, Thomas F. ; Verrey, François ; Matter, Christian M.

In: European Heart Journal, 2013, vol. 34, no. 45, p. 3515-3524

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    Titre
    • Endothelial mineralocorticoid receptor activation mediates endothelial dysfunction in diet-induced obesity
    Auteur
    • Schäfer, Nicola. Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
    • Lohmann, Christine. Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
    • Winnik, Stephan. Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
    • van Tits, Lambertus J.. Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
    • Miranda, Melroy X.. Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
    • Vergopoulos, Athanasios. Institute for Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland
    • Ruschitzka, Frank. Cardiovascular Research and Cardiology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
    • Nussberger, Jürg. Division of Internal Medicine, University of Lausanne, Lausanne, Switzerland
    • Berger, Stefan. German Cancer Research Center, Heidelberg, Germany
    • Lüscher, Thomas F.. Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
    • Verrey, François. Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
    • Matter, Christian M.. Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
    Type de document
    • Postprint
    Langue
    • Anglais
    Publié dans
    • European Heart Journal, 2013, vol. 34, no. 45, p. 3515-3524. Oxford University Press
    Autre version électronique
    Identifiant OAI-PMH
    • oai:doc.rero.ch:291228
    Summary
    Received 22 July 2012; revised 29 January 2013; accepted 4 March 2013Aims 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. Methods and 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. Conclusion 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