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(Circulation Research. 2005;97:236.)
© 2005 American Heart Association, Inc.

Molecular Medicine

Inhibition of Lipopolysaccharide-Induced Inflammatory Responses by an Apolipoprotein AI Mimetic Peptide

Himanshu Gupta^*, Lijun Dai^*, Geeta Datta, David W. Garber, Hernan Grenett, Yanbing Li, Vinod Mishra, Mayakonda N. Palgunachari, Shaila Handattu, Sandra H. Gianturco, William A. Bradley, G.M. Anantharamaiah, C. Roger White

From the Department of Medicine, Division of Cardiovascular Disease (H.G., L.D., H.G., C.R.W.), the Vascular Biology and Hypertension Program (L.D., C.R.W.), and the Atherosclerosis Research Unit (G.D., D.W.G., V.M., M.N.P., S.H., S.H.G., W.A.B., G.M.A.), University of Alabama at Birmingham; and the First Affiliated Hospital of Sun Yat-Sen University (Y.L.), Guangzhou, People’s Republic of China.

Correspondence to C. Roger White, Dept of Medicine, Vascular Biology and Hypertension Program, 1046 Zeigler Research Bldg, 703 S 19th St, Birmingham, AL 35294-0007. E-mail crwhite{at}uab.edu

Previous studies suggest that high-density lipoprotein and apoAI inhibit lipopolysaccharide (LPS)-induced inflammatory responses. The goal of the current study was to test the hypothesis that the apoAI mimetic peptide L-4F exerts antiinflammatory effects similar to apoAI. Pretreatment of human umbilical vein endothelial cells (HUVECs) with LPS induced the adhesion of THP-1 monocytes. Incubation of cells with LPS and L-4F (1 to 50 µg/mL) reduced THP-1 adhesion in a concentration-dependent manner. This response was associated with a significant reduction in the synthesis of cytokines, chemokines, and adhesion molecules. L-4F reduced vascular cell adhesion molecule-1 expression induced by LPS or lipid A, whereas a control peptide (Sc-4F) showed no effect. In contrast to LPS treatment, L-4F did not inhibit IL-1ß- or tumor necrosis factor-–induced vascular cell adhesion molecule-1 expression. The inhibitory effect of L-4F on LPS induction of inflammatory markers was associated with reduced binding of LPS to its plasma carrier molecule, lipopolysaccharide binding protein, and decreased binding of LPS to HUVEC monolayers. LPS and L-4F in HUVEC culture medium were fractionated by fast protein liquid chromatography and were localized to the same fractions, suggesting a physical interaction between these molecules. Proinflammatory responses to LPS are associated with the binding of lipid A to cell surface receptors. The current studies demonstrate that L-4F reduces the expression of inflammatory markers induced by LPS and lipid A and suggest that apoAI peptide mimetics may be useful in the treatment of inflammation associated with endotoxemia.

Key Words: lipopolysaccharide • inflammation • vascular cell adhesion molecule-1 • apolipoprotein AI mimetic peptide

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