title: Inhibition of the renin-angiotensin system abolishes the proatherogenic effect of uremia in apolipoprotein E-deficient mice.
abstract: OBJECTIVE
  Uremia accelerates atherosclerosis in apolipoprotein E-deficient (apoE-/-) mice. We examined whether this effect may be preventable by pharmacological blockade of the renin-angiotensin system (RAS).
  
  
  RESULTS
  Uremia was induced in apoE-/- mice by 5/6 nephrectomy (NX). Treatment with the angiotensin converting enzyme inhibitor enalapril (2 or 12 mg/kg/d) from week 4 to 36 after NX reduced the aortic plaque area fraction from 0.23+/-0.02 (n=20) in untreated mice to 0.11+/-0.01 (n=21) and 0.08+/-0.01 (n=23), respectively (P<0.0001); the aortic plaque area fraction was 0.09+/-0.01 (n=22) in sham-operated controls. Enalapril from week 20 to 44 after NX also retarded the progression of atherosclerosis. Plasma levels of soluble intercellular adhesion molecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (sVCAM-1) and concentrations of IgM antibodies against oxidized low density lipoprotein (OxLDL) increased after NX (P<0.01). Enalapril (12 mg/kg/d) attenuated these increases (P<0.05) and reduced aortic expression of vascular cell adhesion molecule (VCAM)-1 mRNA (P<0.05). Atherosclerosis in NX mice was also reduced by losartan (an angiotensin II receptor-blocker), but not when blood pressure was lowered with hydralazine (a non-RAS-dependent vasodilator).
  
  
  CONCLUSIONS
  The results suggest that inhibition of RAS abolishes the proatherogenic effect of uremia independent of its blood pressure-lowering effect, possibly because of antiinflammatory and antioxidative mechanisms.
authors.affiliation: Dept. of Nephrology P 2131, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. susannebro@dadlnet.dk
authors.forename: Susanne
authors.initials: S
authors.lastname: Bro
authors.forename: Christoph J
authors.initials: CJ
authors.lastname: Binder
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Witztum
authors.forename: Klaus
authors.initials: K
authors.lastname: Olgaard
authors.forename: Lars B
authors.initials: LB
authors.lastname: Nielsen
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000097:blood / Q000276:immunology; D001013:Aorta, Thoracic / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000172:deficiency*; D050197:Atherosclerosis / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D029721:Drosophila Proteins; D004656:Enalapril / Q000494:pharmacology; D005500:Follow-Up Studies; D015870:Gene Expression / Q000187:drug effects; D007074:Immunoglobulin G / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000276:immunology; D019808:Losartan / Q000494:pharmacology; D051379:Mice; D009392:Nephrectomy / Q000009:adverse effects; D010084:Oxidation-Reduction; D007703:Peptidyl-Dipeptidase A / Q000097:blood / Q000187:drug effects; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D011956:Receptors, Cell Surface; D012084:Renin-Angiotensin System / Q000187:drug effects*; D014511:Uremia / Q000097:blood / Q000150:complications* / Q000276:immunology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D000888:Antibodies, Anti-Idiotypic; D001057:Apolipoproteins E; D029721:Drosophila Proteins; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D019010:Vascular Cell Adhesion Molecule-1; C405956:gustatory receptor, Drosophila; C099252:oxidized low density lipoprotein; D018799:Intercellular Adhesion Molecule-1; D004656:Enalapril; D007703:Peptidyl-Dipeptidase A; D019808:Losartan