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(Circulation Research. 2005;97:1190.)
© 2005 American Heart Association, Inc.

Integrative Physiology

Effects of D-4F on Vasodilation and Vessel Wall Thickness in Hypercholesterolemic LDL Receptor–Null and LDL Receptor/Apolipoprotein A-I Double-Knockout Mice on Western Diet

Jingsong Ou^*, Jingli Wang, Hao Xu, Zhijun Ou, Mary G. Sorci-Thomas, Deron W. Jones, Paul Signorino, John C. Densmore, Sushma Kaul, Keith T. Oldham, Kirkwood A. Pritchard, Jr^*

From the Departments of Surgery, Division of Pediatric Surgery (J.O., J.W., H.X., Z.O., D.W.J., P.S., J.C.D., S.K., K.T.O., K.A.P.), Children’s Research Institute (J.O., J.W., H.X., Z.O., P.S., J.C.D., K.T.O., K.A.P.), and Cardiovascular Center (J.O., J.W., H.X., Z.O., K.T.O., K.A.P.), Medical College of Wisconsin, Milwaukee; Guangzhou Institute of Respiratory Disease, Division of Cardiothoracic Surgery (J.O.), and Department of Medicine, Division of Cardiology (Z.O.), The First Affiliated Hospital of Guangzhou Medical College, China; Department of Pathology (M.G.S.-T.), Wake Forest University School of Medicine, Winston-Salem, NC.

Correspondence to Kirkwood A. Pritchard, Jr, PhD, Medical College of Wisconsin, Pediatric Surgery, CRI, CVC, M-4060, 8701 Watertown Plank Rd, Milwaukee, WI 53226. E-mail kpritch{at}mcw.edu

Previously we showed L-4F, a novel apolipoprotein A-I (apoA-I) mimetic, improved vasodilation in 2 dissimilar models of vascular disease: hypercholesterolemic LDL receptor–null (Ldlr^–/–) mice and transgenic sickle cell disease mice. Here we determine the mechanisms by which D-4F improves vasodilation and arterial wall thickness in hypercholesterolemic Ldlr^–/– mice and Ldlr^–/–/apoA-I null (apoA-I^–/–), double-knockout mice. Ldlr^–/– and Ldlr^–/–/apoA-I^–/– mice were fed Western diet (WD) with and without D-4F. Oral D-4F restored endothelium- and endothelial NO synthase (eNOS)-dependent vasodilation in direct relationship to duration of treatments and reduced wall thickness in as little as 2 weeks in vessels with preexisting disease in Ldlr^–/– mice. D-4F had no effect on total or HDL cholesterol concentrations but reduced proinflammatory HDL levels. D-4F had no effect on plasma myeloperoxidase concentrations but reduced myeloperoxidase association with apoA-I as well as 3-nitrotyrosine in apoA-I. D-4F increased endothelium- and eNOS-dependent vasodilation in Ldlr^–/–/apoA-I^–/– mice but did not reduce wall thickness as it had in Ldlr^–/– mice. Vascular endothelial cells were treated with 22(R)-hydroxycholesterol with and without L-4F. 22(R)-Hydroxycholesterol decreased NO (·NO) and increased superoxide anion (O₂^·–) production and increased ATP-binding cassette transporter-1 and collagen expression. L-4F restored ·NO and O₂^·– balance, had little effect on ATP-binding cassette transporter-1 expression, but reduced collagen expression. These data demonstrate that although D-4F restores vascular endothelial cell and eNOS function to increase vasodilation, HDL containing apoA-I, or at least some critical concentration of the antiatherogenic lipoprotein, is required for D-4F to decrease vessel wall thickness.

Key Words: cardiovascular diseases • hypercholesterolemia • lipoproteins • nitric oxide synthase • vasodilation

Related Article:

An Apolipoprotein A-I Mimetic Works Best in the Presence of Apolipoprotein A-I

Mohamad Navab, G.M. Anantharamaiah, and Alan M. Fogelman
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