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      Epithelial sodium channel in aldosterone- induced endothelium stiffness and aortic dysfunction

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          Abstract

          Enhanced activation of the endothelial mineralocorticoid receptor contributes to the development of arterial stiffness, which is an independent predictor of cardiovascular disease. Previously we showed that enhanced endothelium mineralocorticoid receptor signaling in female mice prompts expression and translocation of the alpha subunit of the epithelial sodium channel (ENaC) to the endothelial cell (EC) surface (EnNaC) inducing vascular fibrosis and stiffness. Further, amiloride, an ENaC antagonist, inhibits vascular fibrosis, remodeling, and stiffness induced by feeding a Western diet high in saturated fat and refined carbohydrates. However, how this occurs remains unknown. Thereby, we hypothesized that EC-specific EnNaC activation is necessary for aldosterone mediated endothelium stiffness. To address this notion EnNaC α subunit knock out (EnNaC −/−) and wild type littermate female mice were administrated aldosterone (250 μg/kg/day) via osmotic minipumps for 3 weeks beginning at 25–28 weeks of age. In isolated mouse ECs, inward sodium currents were significantly reduced in amiloride controls as well as in EnNaC −/−. Likewise, aldosterone-induced endothelium stiffness was increased and endothelium dependent relaxation less in EnNaC −/− versus wild type. Further, EnNaC −/− mice exhibited attenuated responses to aldosterone infusion including: aortic endoplasmic reticulum stress, endothelium nitric oxide synthase activation, endothelium permeability, expression of pro-inflammatory cytokines, oxidative stress, and aortic collagen 1 deposition, supporting the notion that αEnNaC subunit activation contributes to these vascular responses.

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          Author and article information

          Journal
          7906255
          4217
          Hypertension
          Hypertension
          Hypertension (Dallas, Tex. : 1979)
          0194-911X
          1524-4563
          13 June 2018
          September 2018
          01 September 2019
          : 72
          : 3
          : 731-738
          Affiliations
          [1 ]Diabetes and Cardiovascular Research Center, University of Missouri School of Medicine, Columbia, MO, 65212, USA
          [2 ]Research Service, Harry S Truman Memorial Veterans Hospital, Research Service, 800 Hospital Dr, Columbia, MO, 65201, USA
          [3 ]Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO, 65212, USA
          [4 ]Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, 65212, USA
          [5 ]INSERM, UMR_S 1138, Team 1, Centre de Recherche des Cordeliers, UPMC Univ Paris 06, Université Paris Descartes, F-75006, Paris, France
          Author notes
          [* ]Corresponding Author: Guanghong Jia, PhD or James R. Sowers, MD, Diabetes and Cardiovascular Research Center, University of Missouri School of Medicine, D109 Diabetes Center HSC, One Hospital Drive, Columbia, MO 65212, Phone: (573) 884-0769; Fax: (573) 884-5530, Jiag@ 123456health.missouri.edu or Sowersj@ 123456health.missouri.edu
          [&]

          Authors contributed equally to this work

          Article
          PMC6202124 PMC6202124 6202124 nihpa974889
          10.1161/HYPERTENSIONAHA.118.11339
          6202124
          29987101
          cb63eead-7e68-4527-bc44-661831c58914
          History
          Categories
          Article

          inflammation,endothelial stiffness,epithelial sodium channel,aldosterone,Arterial stiffness

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