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J. Biol. Chem., Vol. 282, Issue 3, 1980-1988, January 19, 2007

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ApoA-I Mimetic Peptides with Differing Ability to Inhibit Atherosclerosis Also Exhibit Differences in Their Interactions with Membrane Bilayers^*

Shaila P. Handattu, David W. Garber¹, Dawn C. Horn, Donald W. Hughes, Bob Berno, Alex D. Bain, Vinod K. Mishra, Mayakonda N. Palgunachari, Geeta Datta, G. M. Anantharamaiah, and Richard M. Epand²

From the Departments of Medicine, Biochemistry, and Molecular Genetics and the Atherosclerosis Research Unit, University of Alabama at Birmingham, Birmingham, Alabama 35294 and the Department of Biochemistry and Biomedical Sciences and Department of Chemistry, McMaster University, Hamilton, L8N 3Z5 Ontario, Canada

Two homologous apoA-I mimetic peptides, 3F-2 and 3F¹⁴, differ in their in vitro antiatherogenic properties (Epand, R. M., Epand, R. F., Sayer, B. G., Datta, G., Chaddha, M., and Anantharamaiah, G. M. (2004) J. Biol. Chem. 279, 51404-51414). In the present work, we demonstrate that the peptide 3F-2, which has more potent anti-inflammatory activity in vitro when administered intraperitoneally to female apoE null mice (20 µg/mouse/day) for 6 weeks, inhibits atherosclerosis (lesion area 15,800 ± 1000 µm², n = 29), whereas 3F¹⁴ does not (lesion area 20,400 ± 1000 µm², n = 26) compared with control saline administered (19,900 ± 1400 µm², n = 22). Plasma distribution of the peptides differs in that 3F-2 preferentially associates with high density lipoprotein, whereas 3F¹⁴ preferentially associates with apoB-containing particles. After intraperitoneal injection of ¹⁴C-labeled peptides, 3F¹⁴ reaches a higher maximal concentration and has a longer half-time of elimination than 3F-2. A study of the effect of these peptides on the motional and organizational properties of phospholipid bilayers, using several NMR methods, demonstrates that the two peptides insert to different extents into membranes. 3F-2 with aromatic residues at the center of the nonpolar face partitions closer to the phospholipid head group compared with 3F¹⁴. In contrast, only 3F¹⁴ affects the terminal methyl group of the acyl chain, decreasing the ²H order parameter and at the same time also decreasing the molecular motion of this methyl group. This dual effect of 3F¹⁴ can be explained in terms of the cross-sectional shape of the amphipathic helix. These results support the proposal that the molecular basis for the difference in the biological activities of the two peptides lies with their different interactions with membranes.

Received for publication, June 29, 2006 , and in revised form, November 13, 2006.

^* This work was supported in part by Canadian Institutes for Health Research Grant MT-7654 and National Institutes of Health Grant HL 34343. G. M. A. is a Principal in Bruin Pharma, LA, a startup biotech company. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables S4-S7.

¹ To whom correspondence may be addressed: Dept. of Medicine, UAB Medical Center, Birmingham, AL 35294. Tel.: 205-934-1218; Fax: 205-975-8079; E-mail: dgarber{at}uab.edu.

² To whom correspondence may be addressed: Dept. of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8N 3Z5, Canada. Tel.: 905-525-9140; Fax: 905-521-1397; E-mail: epand{at}mcmaster.ca.

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