title: FAD286, an aldosterone synthase inhibitor, reduced atherosclerosis and inflammation in apolipoprotein E-deficient mice.
abstract: BACKGROUND
  Aldosterone is known to be involved in atherosclerosis and cardiovascular disease and blockade of its receptor was shown to improve cardiovascular function. It was, therefore, hypothesized that inhibition of aldosterone synthesis would also reduce atherosclerosis development.
  
  
  METHODS
  To test this hypothesis, we examined the effect of FAD286 (FAD), an aldosterone synthase inhibitor, on the development of atherosclerosis in spontaneous atherosclerotic apolipoprotein E-deficient mice. Mice were divided into three treatment groups: normal diet, low-salt diet (LSD) and LSD treated with FAD at 30 mg/kg per day (LSD + FAD) for 10 weeks.
  
  
  CONCLUSIONS
  Histomorphometry of the aortas obtained from these mice showed that atherosclerotic lesion area increased by three-fold under LSD compared with normal diet and FAD significantly reduced lesion area to values similar to normal diet. Changes in atherosclerosis were paralleled by changes in the expression of the inflammation markers (C-reactive protein, monocyte chemotactic protein-1, interleukin-6, nuclear factor kappa B and intercellular adhesion molecule-1) in peritoneal macrophages obtained from these mice. Surprisingly, whereas LSD increased serum or urine aldosterone levels, FAD did not alter these levels when evaluated at the end of the study. In J774A.1 macrophage-like cell line stimulated with lipopolysaccharide, FAD was shown to have a direct dose-dependent anti-inflammatory effect. In apolipoprotein E-deficient mice, FAD reduces atherosclerosis and inflammation. However, these actions appeared to be dissociated from its effect on inhibition of aldosterone synthesis.
authors.affiliation: Lipid Research Laboratory, Technion Rappaport Faculty of Medicine and Rambam Medical Center, Haifa, Israel.
authors.forename: Aviva
authors.initials: A
authors.lastname: Gamliel-Lazarovich
authors.forename: Anna
authors.initials: A
authors.lastname: Gantman
authors.forename: Raymond
authors.initials: R
authors.lastname: Coleman
authors.forename: Arco Y
authors.initials: AY
authors.lastname: Jeng
authors.forename: Marielle
authors.initials: M
authors.lastname: Kaplan
authors.forename: Shlomo
authors.initials: S
authors.lastname: Keidar
mesh_terms: D000450:Aldosterone / Q000097:blood; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002460:Cell Line; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors*; D004039:Diet, Sodium-Restricted; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D017316:Fadrozole; D007093:Imidazoles / Q000494:pharmacology*; D007249:Inflammation / Q000378:metabolism / Q000517:prevention & control*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011725:Pyridines / Q000494:pharmacology*
chemical_list: D001057:Apolipoproteins E; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D000450:Aldosterone; D019405:Cytochrome P-450 CYP11B2; D017316:Fadrozole