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

被引:89
作者
d'Uscio, LV
Smith, LA
Katusic, ZS
机构
[1] Mayo Clin & Mayo Fdn, Dept Anesthesiol, Rochester, MN 55905 USA
[2] Mayo Clin & Mayo Fdn, Dept Mol Pharmacol & Expt Therapeut, Rochester, MN 55905 USA
关键词
apolipoproteins; carotid arteries; endothelium; nitric oxide; superoxides; mice;
D O I
10.1161/hs1101.097393
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
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 mum) 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 N-w-nitro-L-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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页码:2658 / 2664
页数:7
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