title: Essential role of ICAM-1 in aldosterone-induced atherosclerosis.
abstract: OBJECTIVE
  Elevated aldosterone is associated with increased risk of atherosclerosis complications, whereas treatment with mineralocorticoid receptor (MR) antagonists decreases the rate of cardiovascular events. Here we test the hypothesis that aldosterone promotes early atherosclerosis by modulating intercellular adhesion molecule-1 (ICAM-1) expression and investigate the molecular mechanisms by which aldosterone regulates ICAM-1 expression.
  
  
  RESULTS
  Apolipoprotein-E (ApoE)-/-mice fed an atherogenic diet and treated with aldosterone for 4weeks showed increased vascular expression of ICAM-1, paralleled by enhanced atherosclerotic plaque size in the aortic root. Moreover, aldosterone treatment resulted in increased plaque lipid and inflammatory cell content, consistent with an unstable plaque phenotype. ApoE/ICAM-1 double knockout (ApoE-/-/ICAM-1-/-) littermates were protected from the aldosterone-induced increase in plaque size, lipid content and macrophage infiltration. Since aldosterone is known to regulate ICAM-1 transcription via MR in human endothelial cells, we explored MR regulation of the ICAM-1 promoter. Luciferase reporter assays performed in HUVECs using deletion constructs of the human ICAM-1 gene promoter showed that a region containing a predicted MR-responsive element (MRE) is required for MR-dependent transcriptional regulation of ICAM-1.
  
  
  CONCLUSIONS
  Pro-atherogenic effects of aldosterone are mediated by increased ICAM-1 expression, through transcriptional regulation by endothelial MR. These data enhance our understanding of the molecular mechanism by which MR activation promotes atherosclerosis complications.
authors.affiliation: Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Pisana, 00166 Rome, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Marzolla
authors.affiliation: Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Pisana, 00166 Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Armani
authors.affiliation: Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Pisana, 00166 Rome, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Mammi
authors.affiliation: Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA, USA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Moss
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy; Laboratory of Neuroembryology, Fondazione Santa Lucia, 00143 Rome, Italy.
authors.forename: Vittoria
authors.initials: V
authors.lastname: Pagliarini
authors.affiliation: Laboratory of Pathophysiology of Cachexia and Metabolism of Skeletal Muscle, IRCCS San Raffaele Pisana, 00166 Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Pontecorvo
authors.affiliation: Interinstitutional Multidisciplinary Biobank (BioBIM), IRCCS San Raffaele Pisana, 00166 Rome, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Antelmi
authors.affiliation: Department of Systems Medicine, Endocrinology Unit, S. Eugenio & CTO A. Alesini Hospitals-ASL RM2, University Tor Vergata, Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Fabbri
authors.affiliation: Cardiovascular & Cell Science Institute, St George's Hospital NHS Trust, University of London, London, United Kingdom; Department of Medical Sciences, IRCCS San Raffaele, Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Rosano
authors.affiliation: Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA, USA.
authors.forename: Iris Z
authors.initials: IZ
authors.lastname: Jaffe
authors.affiliation: Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Pisana, 00166 Rome, Italy; Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, 00166 Rome, Italy. Electronic address: massimiliano.caprio@sanraffaele.it.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Caprio
mesh_terms: D000450:Aldosterone / Q000633:toxicity; D000818:Animals; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D005838:Genotype; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012313:RNA / Q000235:genetics*; D018161:Receptors, Mineralocorticoid / Q000378:metabolism
chemical_list: D018161:Receptors, Mineralocorticoid; D018799:Intercellular Adhesion Molecule-1; D000450:Aldosterone; D012313:RNA
keywords: Aldosterone; Atherosclerosis; Endothelial cells; Intercellular adhesion molecule-1; Mineralocorticoid receptor