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L-4F, an apolipoprotein A-1 mimetic, dramatically improves vasodilation in hypercholesterolemia and sickle cell disease. Circulation 2003 May 13;107(18):2337-41

Date

05/07/2003

Pubmed ID

12732610

DOI

10.1161/01.CIR.0000070589.61860.A9

Scopus ID

2-s2.0-0037986617   116 Citations

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.

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.

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.

Author List

Ou J, Ou Z, Jones DW, Holzhauer S, Hatoum OA, Ackerman AW, Weihrauch DW, Gutterman DD, Guice K, Oldham KT, Hillery CA, Pritchard KA Jr

Authors

David D. Gutterman MD Sr Associate Director, Professor in the Medicine department at Medical College of Wisconsin
Keith T. Oldham MD Professor in the Surgery department at Medical College of Wisconsin
Kirkwood A. Pritchard PhD Professor in the Surgery department at Medical College of Wisconsin
Dorothee Weihrauch DVM, PhD Professor in the Anesthesiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Anemia, Sickle Cell
Animals
Apolipoprotein A-I
Arterioles
Cells, Cultured
Endothelium, Vascular
Hypercholesterolemia
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Molecular Mimicry
Peptides
Receptors, LDL
Superoxides
Vasodilation
jenkins-FCD Prod-403 0f9a74600e4e79798f8fa6f545ea115f3dd948b2