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Endothelin ETA receptor blobkade restores NU-mediated endothelial function and inhibits atheroscierosis apolipoprotein E-deficient mice
- Source :
- Proceedings of the National Academy of Sciences of the United States. Nov 24, 1998, Vol. 95 Issue 24, p14367, 6 p.
- Publication Year :
- 1998
-
Abstract
- This study investigated whether endothelin-1 (ET-1), a potent vasoconstrictor, which also stimulates cell proliferation, contributes to endothelial dysfunction and atherosclerosis. Apolipoprotein E (apoE)-deficient mice and C57BL/6 control mice were treated with a Western-type diet to accelerate atherosclerosis with or without ETA receptor antagonist LU135252 (50 mg/kg/d) for 30 wk. Systolic blood pressure, plasma lipid profile, and plasma nitrate levels were determined. In the aorta, NO-mediated endothelium-dependent relaxation, atheroma formation, ET receptor-binding capacity, and vascular ET-1 protein content were assessed. In apoE-deficient but not C57BL/6 mice, severe atherosclerosis developed within 30 wk. Aortic ET-1 protein content (P < 0.0001) and binding capacity for ETA receptors was increased as compared with C57BL/6 mice. In contrast, NO-mediated, endothelium-dependent relaxation to acetylcholine (56 [+ or -] 3 vs. 99 [+ or -] 2%, P < 0.0001) and plasma nitrate were reduced (57.9 [+ or -] 4 vs. 93 [+ or -] 10 [[micro]mol]/liter, P < 0.01). Treatment with the ETA receptor antagonist LU135252 for 30 wk had no effect on the lipid profile or systolic blood pressure in apoE-deficient mice, but increased NO-mediated endothelium-dependent relaxation (from 56 [+ or -] 3 to 93 [+ or -] 2%, P < 0.0001 vs. untreated) as well as circulating nitrate levels (from 57.9 [+ or -] 4 to 80 [+ or -] 8.3 [[micro]mol]/liter, P < 0.05). Chronic ETA receptor blockade reduced elevated tissue ET-1 levels comparable with those found in C57BL/6 mice and inhibited atherosclerosis in the aorta by 31% without affecting plaque morphology or ET receptor-binding capacity. Thus, chronic [ET.sub.A] receptor blockade normalizes NO-mediated endothelial dysfunction and reduces atheroma formation independent of plasma cholesterol and blood pressure in a mouse model of human atherosclerosis. [ET.sub.A] receptor blockade may have therapeutic potential in patients with atherosclerosis.
Details
- ISSN :
- 00278424
- Volume :
- 95
- Issue :
- 24
- Database :
- Gale General OneFile
- Journal :
- Proceedings of the National Academy of Sciences of the United States
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.57877438