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 language | English (US) |
|---|---|
| Pages (from-to) | 2658-2664 |
| Number of pages | 7 |
| Journal | Stroke |
| Volume | 32 |
| Issue number | 11 |
| State | Published - 2001 |
Fingerprint
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 journal › Article
}
TY - JOUR
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.
KW - Apolipoproteins
KW - Carotid arteries
KW - Endothelium
KW - Mice
KW - Nitric oxide
KW - Superoxides
UR - http://www.scopus.com/inward/record.url?scp=0035172979&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0035172979&partnerID=8YFLogxK
M3 - Article
C2 - 11692031
AN - SCOPUS:0035172979
VL - 32
SP - 2658
EP - 2664
JO - Stroke
JF - Stroke
SN - 0039-2499
IS - 11
ER -