title: Long-term application of the aldosterone antagonist spironolactone prevents stiff endothelial cell syndrome.
abstract: Aldosterone triggers the stiff endothelial cell syndrome (SECS), characterized by an up-regulation of epithelial sodium channels (ENaCs) and mechanical stiffening of the endothelial cell cortex accompanied by endothelial dysfunction. In vivo, aldosterone antagonism exerts sustained protection on the cardiovascular system. To illuminate the molecular mechanisms of this time-dependent effect, a study on endothelial cells in vitro and ex vivo was designed to investigate SECS over time. Endothelia (from human umbilical veins, bovine aortae, and explants of human arteries) were cultured in aldosterone-supplemented medium with or without the mineralocorticoid receptor (MR) antagonist spironolactone. MR expression, ENaC expression, cortical stiffness, and shear-mediated nitric oxide (NO) release were determined after 3 d (short term) and up to 24 d (long term). Over time, MR expression increased by 129%. ENaC expression and surface abundance increased by 32% and 42% (13.8 to 19.6 molecules per cell surface), paralleled by a 49% rise in stiffness. Spironolactone prevented this development and, after 3 wk of treatment, increased NO release by 50%. Thus, spironolactone improves endothelial function long-lastingly by preventing a time-dependent manifestation of SECS. This emphasizes the key role of vascular endothelium as a therapeutical target in cardiovascular disorders and might explain blood pressure independent actions of MR antagonism.
authors.affiliation: Institute of Physiology II, University of Münster, Münster, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Drüppel
authors.forename: Kristina
authors.initials: K
authors.lastname: Kusche-Vihrog
authors.forename: Claudia
authors.initials: C
authors.lastname: Grossmann
authors.forename: Michael
authors.initials: M
authors.lastname: Gekle
authors.forename: Bernd
authors.initials: B
authors.lastname: Kasprzak
authors.forename: Eva
authors.initials: E
authors.lastname: Brand
authors.forename: Hermann
authors.initials: H
authors.lastname: Pavenstädt
authors.forename: Hans
authors.initials: H
authors.lastname: Oberleithner
authors.forename: Katrin
authors.initials: K
authors.lastname: Kliche
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D053503:Epithelial Sodium Channels / Q000378:metabolism*; D006801:Humans; D018625:Microscopy, Atomic Force; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D013148:Spironolactone / Q000494:pharmacology*; D014471:Umbilical Veins / Q000187:drug effects / Q000378:metabolism
chemical_list: D053503:Epithelial Sodium Channels; D000451:Mineralocorticoid Receptor Antagonists; D013148:Spironolactone; D009569:Nitric Oxide
keywords: ENaC; atomic force microscopy; endothelial function; epithelial sodium channel; mechanical stiffness