title: Improvement of endothelial function in a murine model of mild cholesterol-induced atherosclerosis by mineralocorticoid antagonism.
abstract: The renin-angiotensin-aldosterone-system (RAAS) plays a role in endothelial dysfunction and atherosclerosis. During treatment with RAAS-inhibitors, elevated aldosterone may sustain "aldosterone escape".
  
  
  
  We investigated the effects of treatment with the mineralocorticoid antagonist eplerenone (Ep) compared with ramipril (Rami) or the combination of both on oxidative stress, plaque formation and endothelial function, in atherosclerotic apolipoprotein E deficient mice (ApoE(-/-)-mice). ApoE(-/-)-mice were fed a cholesterol rich diet (21% fat, 19.5% casein, 1.25% cholesterol) for 8 weeks to produce mild atherosclerosis (i.e. plaque load 20-30%). ApoE(-/-)-mice (control), ApoE(-/-)-mice treated with Ep (25 mg/kg/day), Rami (2.5 mg/kg/day) and their combination were compared. Heart rate (HR) and blood pressure (BP) were measured using the tail-cuff-method. Endothelial function was measured in aortic rings and corpora cavernosal strips (CCs). Atherosclerotic plaque burden, collagen content, oxidative stress (Dihydroethidium (DHE) staining) and macrophages were determined.
  
  
  
  Treatments had no effects on HR and slightly reduced BP in ApoE(-/-)-mice treated with the combination of eplerenone and ramipril. Endothelium-dependent relaxation of aortic rings and CCs with carbachol was significantly improved in animals treated with Ep, Rami or their combination (p = 0.05 - p = 0.001). DHE-stained penile and aortic sections revealed a significant reduction in superoxide production in all treated groups (p = 0.035 - p = 0.001). In parallel, aortic and penile collagen content in ApoE(-/-)-mice was significantly decreased (p = 0.035 - p < 0.001) in animals treated with Ep, Rami or their combination. In agreement, there was a trend towards a reduction of aortic plaque area by treatment with Ep (-9.0 ± 3.2%) and Rami (-11.9 ± 4%). Only the treatment with the combination induced a significant reduction of the atherosclerotic plaque burden (p = 0.045). Moreover, the treatment of ApoE(-/-)-mice with Ep, Rami and their combination significantly reduced the count macrophage count in atherosclerotic plaque lesions. Ep restored endothelial function by reduction of oxidative stress, atherosclerotic macrophage content, atherosclerotic lesion size and fibrosis to the same extent as treatment with Rami or the combination.
  
  
  
  Mineralocorticoid antagonism provides vasculoprotective effects and should be clinically evaluated for vascular disease such as erectile dysfunction.
authors.affiliation: Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Kirrberger Straße 100, D-66421, Homburg, Saar, Germany. Electronic address: mario.kratz@uks.eu.
authors.forename: Mario T
authors.initials: MT
authors.lastname: Kratz
authors.affiliation: Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Kirrberger Straße 100, D-66421, Homburg, Saar, Germany.
authors.forename: Stephan H
authors.initials: SH
authors.lastname: Schirmer
authors.affiliation: Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Kirrberger Straße 100, D-66421, Homburg, Saar, Germany.
authors.forename: Magnus
authors.initials: M
authors.lastname: Baumhäkel
authors.affiliation: Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Kirrberger Straße 100, D-66421, Homburg, Saar, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Böhm
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism*; D001794:Blood Pressure; D002784:Cholesterol / Q000008:administration & dosage*; D004730:Endothelium, Vascular / Q000502:physiology*; D007172:Erectile Dysfunction / Q000378:metabolism; D006339:Heart Rate; D008297:Male; D051379:Mice; D000074085:Mice, Knockout, ApoE; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D008901:Mineralocorticoids; D018384:Oxidative Stress
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000451:Mineralocorticoid Receptor Antagonists; D008901:Mineralocorticoids; D002784:Cholesterol
keywords: Atherosclerosis; Corpora cavernosa; Endothelial dysfunction; Erectile dysfunction; Oxidative stress; Vascular and penile fibrosis