Hypercholesterolemia impairs endothelium-dependent relaxations in common carotid arteries of apolipoprotein E-deficient mice

Livius V. D'Uscio, Leslie A. Smith, Zvonimir S. Katusic

Research output: Contribution to journalArticle

76 Scopus citations

Abstract

Background and Purpose - The effects of Western-type fat diet on endothelium-dependent relaxations and vascular structure in carotid arteries from a mouse model of human atherosclerosis are not known. Our objective was to characterize the mechanisms underlying endothelial dysfunction in apoE-deficient mice. Methods - C57BL/6J and apoE-deficient mice were fed for 26 weeks with a lipid-rich Western-type diet. Changes in the intraluminal diameter of pressurized common carotid arteries (ID 450 μm) were measured in vitro with a video dimension analyzer. Endothelial NO synthase protein content was evaluated by Western blotting. Intracellular cGMP and cAMP levels were determined by radioimmunoassay. Results - No morphological changes were observed in the carotid arteries of apoE-deficient mice. However, endothelium-dependent relaxations to acetylcholine (10-9 to 10-5 mol/L) were impaired (maximal relaxation 52±7% versus 83±5% for control mice, P<0.05). Treatment of arteries with NO synthase inhibitor Nω-nitro-ω-arginine methyl ester inhibited relaxations to acetylcholine to the same extent in apoE-deficient mice as in control mice. Preincubation of carotid arteries with cell-permeable superoxide dismutase mimetic Mn(III) tetra(4-benzoic acid)porphyrin chloride almost normalized NO-mediated relaxations to acetylcholine (75±5%, P<0.05). Endothelium-dependent relaxations to calcium ionophore and endothelium-independent relaxations to NO donor diethylammonium(Z)-1-(N,N-diethylamino) diazen-1-ium-1,2-diolate were unchanged in apoE-deficient mice. In addition, no changes in endothelial NO synthase protein expression and cGMP/cAMP levels were found in carotid arteries of apoE-deficient mice. Conclusions - In carotid arteries of apoE-deficient mice, hypercholesterolemia causes impairment of receptor-mediated activation of eNOS. Increased superoxide anion production in endothelial cells appears to be coupled to activation of cholinergic receptors and is responsible for hypercholesterolemia-induced endothelial dysfunction. The apoE-deficient mouse carotid artery is a valuable new experimental model of endothelial dysfunction.

Original languageEnglish (US)
Pages (from-to)2658-2664
Number of pages7
JournalStroke
Volume32
Issue number11
DOIs
StatePublished - Jan 1 2001

Keywords

  • Apolipoproteins
  • Carotid arteries
  • Endothelium
  • Mice
  • Nitric oxide
  • Superoxides

ASJC Scopus subject areas

  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine
  • Advanced and Specialized Nursing

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