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(Circulation. 2003;107:2337.)
© 2003 American Heart Association, Inc.

Basic Science Reports

L-4F, an Apolipoprotein A-1 Mimetic, Dramatically Improves Vasodilation in Hypercholesterolemia and Sickle Cell Disease

Jingsong Ou, MD, PhD; Zhijun Ou, MD; Deron W. Jones, BA; Sandra Holzhauer, BS; Ossama A. Hatoum, MD; Allan W. Ackerman, MS; Dorothee W. Weihrauch, DVM, PhD; David D. Gutterman, MD; Karen Guice, MD; Keith T. Oldham, MD; Cheryl A. Hillery, MD; Kirkwood A. Pritchard, Jr, PhD

From the Division of Pediatric Surgery, Departments of Surgery (J.O., Z.O., D.W.J., A.W.A., K.G., K.T.O., K.A.P.), Pediatrics (S.H., C.A.H.), Internal Medicine (O.A.H., D.D.G.), Pharmacology and Toxicology (K.A.P.), and Anesthesiology (D.W.W.); the Cardiovascular Center (J.O., Z.O., O.A.H., D.D.G., K.G., K.T.O., K.A.P.); Free Radical Research Center (D.D.G., K.G., K.T.O., K.A.P.); and Blood Research Institute (C.A.H.); Medical College of Wisconsin, Milwaukee.

Correspondence to Kirkwood A. Pritchard Jr, PhD, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226. E-mail kpritch{at}mcw.edu

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.

Key Words: apolipoproteins • vasodilation • endothelium • hypercholesterolemia • anemia, sickle cell

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