Inhibition of the renin-angiotensin system abolishes the proatherogenic effect of uremia in apolipoprotein E-deficient mice

Arterioscler Thromb Vasc Biol. 2007 May;27(5):1080-6. doi: 10.1161/ATVBAHA.107.139634. Epub 2007 Mar 8.

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).

Methods and 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).

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II Type 1 Receptor Blockers / pharmacology*
  • Angiotensin-Converting Enzyme Inhibitors / pharmacology*
  • Animals
  • Antibodies, Anti-Idiotypic / blood
  • Antibodies, Anti-Idiotypic / immunology
  • Aorta, Thoracic / metabolism
  • Aorta, Thoracic / pathology
  • Aortic Diseases / blood
  • Aortic Diseases / etiology
  • Aortic Diseases / prevention & control*
  • Apolipoproteins E / deficiency*
  • Atherosclerosis / blood
  • Atherosclerosis / etiology
  • Atherosclerosis / prevention & control*
  • Blood Pressure / drug effects
  • Disease Models, Animal
  • Disease Progression
  • Drosophila Proteins
  • Enalapril / pharmacology
  • Follow-Up Studies
  • Gene Expression / drug effects
  • Immunoglobulin G / immunology
  • Immunoglobulin M / immunology
  • Intercellular Adhesion Molecule-1 / genetics
  • Intercellular Adhesion Molecule-1 / metabolism
  • Lipoproteins, LDL / immunology
  • Losartan / pharmacology
  • Mice
  • Nephrectomy / adverse effects
  • Oxidation-Reduction
  • Peptidyl-Dipeptidase A / blood
  • Peptidyl-Dipeptidase A / drug effects
  • Prognosis
  • RNA, Messenger / genetics
  • Receptors, Cell Surface
  • Renin-Angiotensin System / drug effects*
  • Uremia / blood
  • Uremia / complications*
  • Uremia / immunology
  • Vascular Cell Adhesion Molecule-1 / genetics
  • Vascular Cell Adhesion Molecule-1 / metabolism

Substances

  • Angiotensin II Type 1 Receptor Blockers
  • Angiotensin-Converting Enzyme Inhibitors
  • Antibodies, Anti-Idiotypic
  • Apolipoproteins E
  • Drosophila Proteins
  • Immunoglobulin G
  • Immunoglobulin M
  • Lipoproteins, LDL
  • RNA, Messenger
  • Receptors, Cell Surface
  • Vascular Cell Adhesion Molecule-1
  • gustatory receptor, Drosophila
  • oxidized low density lipoprotein
  • Intercellular Adhesion Molecule-1
  • Enalapril
  • Peptidyl-Dipeptidase A
  • Losartan