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

75 Citations (Scopus)

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
StatePublished - 2001

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Common Carotid Artery
Apolipoproteins E
Hypercholesterolemia
Endothelium
Carotid Arteries
Nitric Oxide Synthase
Acetylcholine
Benzoic Acid
Calcium Ionophores
Porphyrins
Cholinergic Receptors
Vasodilation
Superoxides
Superoxide Dismutase
Radioimmunoassay
Chlorides
Atherosclerosis
Proteins
Theoretical Models
Endothelial Cells

Keywords

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

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Neuroscience(all)
  • Medicine(all)

Cite this

Hypercholesterolemia impairs endothelium-dependent relaxations in common carotid arteries of apolipoprotein E-deficient mice. / D'Uscio, Livius V.; Smith, Leslie A.; Katusic, Zvonimir S.

In: Stroke, Vol. 32, No. 11, 2001, p. 2658-2664.

Research output: Contribution to journalArticle

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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.",
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T1 - Hypercholesterolemia impairs endothelium-dependent relaxations in common carotid arteries of apolipoprotein E-deficient mice

AU - D'Uscio, Livius V.

AU - Smith, Leslie A.

AU - Katusic, Zvonimir S

PY - 2001

Y1 - 2001

N2 - 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.

AB - 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.

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KW - Carotid arteries

KW - Endothelium

KW - Mice

KW - Nitric oxide

KW - Superoxides

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