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


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.
Division of Pediatric Surgery, Department of Surgery, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226, USA.
Jingsong
J
Ou
Zhijun
Z
Ou
Deron W
DW
Jones
Sandra
S
Holzhauer
Ossama A
OA
Hatoum
Allan W
AW
Ackerman
Dorothee W
DW
Weihrauch
David D
DD
Gutterman
Karen
K
Guice
Keith T
KT
Oldham
Cheryl A
CA
Hillery
Kirkwood A
KA
Pritchard
D000755:Anemia, Sickle Cell / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D016632:Apolipoprotein A-I / Q000737:chemistry; D001160:Arterioles / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D006937:Hypercholesterolemia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018716:Molecular Mimicry; D010455:Peptides / Q000627:therapeutic use*; D011973:Receptors, LDL / Q000235:genetics; D013481:Superoxides / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects*
D016632:Apolipoprotein A-I; C472885:L-4F peptide; D010455:Peptides; D011973:Receptors, LDL; D013481:Superoxides