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L-4F, an apolipoprotein A-1 mimetic, dramatically improves vasodilation in hypercholesterolemia and sickle cell disease.
- Source :
-
Circulation [Circulation] 2003 May 13; Vol. 107 (18), pp. 2337-41. Date of Electronic Publication: 2003 May 05. - Publication Year :
- 2003
-
Abstract
- Background: 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.<br />Methods and Results: 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.<br />Conclusions: 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.
- Subjects :
- Anemia, Sickle Cell drug therapy
Anemia, Sickle Cell metabolism
Animals
Apolipoprotein A-I chemistry
Arterioles drug effects
Arterioles metabolism
Arterioles physiopathology
Cells, Cultured
Endothelium, Vascular drug effects
Endothelium, Vascular physiopathology
Hypercholesterolemia drug therapy
Hypercholesterolemia metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Molecular Mimicry
Receptors, LDL genetics
Superoxides metabolism
Anemia, Sickle Cell physiopathology
Hypercholesterolemia physiopathology
Peptides therapeutic use
Vasodilation drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4539
- Volume :
- 107
- Issue :
- 18
- Database :
- MEDLINE
- Journal :
- Circulation
- Publication Type :
- Academic Journal
- Accession number :
- 12732610
- Full Text :
- https://doi.org/10.1161/01.CIR.0000070589.61860.A9