L-4F, an apolipoprotein A-1 mimetic, dramatically improves vasodilation in hypercholesterolemia and sickle cell disease

Hypercholesterolemia and sickle cell disease (SCD) impair endothelium-dependent vasodilation by dissimilar mechanisms. Hypercholesterolemia impairs vasodilation by a low-density lipoprotein (LDL)-dependent mechanism. SCD has been characterized as a chronic state of inflammation in which xanthine oxi...

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Bibliographic Details
Published in:Circulation (New York, N.Y.) N.Y.), 2003-05, Vol.107 (18), p.2337-2341
Main Authors: JINGSONG OU, ZHIJUN OU, HILLERY, Cheryl A, PRITCHARD, Kirkwood A, JONES, Deron W, HOLZHAUER, Sandra, HATOUM, Ossama A, ACKERMAN, Allan W, WEIHRAUCH, Dorothee W, GUTTERMAN, David D, GUICE, Karen, OLDHAM, Keith T
Format: Article
Language:English
Subjects:
Anemia, Sickle Cell - drug therapy
Anemia, Sickle Cell - metabolism
Anemia, Sickle Cell - physiopathology
Animals
Apolipoprotein A-I - chemistry
Arterioles - drug effects
Arterioles - metabolism
Arterioles - physiopathology
Biological and medical sciences
Cardiovascular system
Cells, Cultured
Endothelium, Vascular - drug effects
Endothelium, Vascular - physiopathology
Hypercholesterolemia - drug therapy
Hypercholesterolemia - metabolism
Hypercholesterolemia - physiopathology
Male
Medical sciences
Mice
Mice, Inbred C57BL
Mice, Knockout
Miscellaneous
Molecular Mimicry
Peptides - therapeutic use
Pharmacology. Drug treatments
Receptors, LDL - genetics
Superoxides - metabolism
Vasodilation - drug effects
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Summary:Hypercholesterolemia and sickle cell disease (SCD) impair endothelium-dependent vasodilation by dissimilar mechanisms. Hypercholesterolemia impairs vasodilation by a low-density lipoprotein (LDL)-dependent mechanism. SCD has been characterized as a chronic state of inflammation in which xanthine oxidase (XO) from ischemic tissues increases vascular superoxide anion (O2*-) generation. Recent reports indicate that apolipoprotein (apo) A-1 mimetics inhibit atherosclerosis in LDL receptor-null (Ldlr-/-) mice fed Western diets. Here we hypothesize that L-4F, an apoA-1 mimetic, preserves vasodilation in hypercholesterolemia and SCD by decreasing mechanisms that increase O2*- generation. Arterioles were isolated from hypercholesterolemic Ldlr-/- mice and from SCD mice that were treated with either saline or L-4F (1 mg/kg per day). Vasodilation in response to acetylcholine was determined by videomicroscopy. Effects of L-4F on LDL-induced increases in endothelium-dependent O2*- generation were determined on arterial segments via the hydroethidine assay and on stimulated endothelial cell cultures via superoxide dismutase-inhibitable ferricytochrome c reduction. Effects of L-4F on XO bound to pulmonary arterioles and content in livers of SCD mice were determined by immunofluorescence. Hypercholesterolemia impaired vasodilation in Ldlr-/- mice, which L-4F dramatically improved. L-4F inhibited LDL-induced increases in O2*- in arterial segments and in stimulated cultures. SCD impaired vasodilation, increased XO bound to pulmonary endothelium, and decreased liver XO content. L-4F dramatically improved vasodilation, decreased XO bound to pulmonary endothelium, and increased liver XO content compared with levels in untreated SCD mice. These data show that L-4F protects endothelium-dependent vasodilation in hypercholesterolemia and SCD. Our findings suggest that L-4F restores vascular endothelial function in diverse models of disease and may be applicable to treating a variety of vascular diseases.
ISSN:0009-7322
1524-4539
DOI:10.1161/01.CIR.0000070589.61860.A9