This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 97/6/524    most recent 01.RES.0000181229.69508.2fv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Navab, M. Articles by Fogelman, A. M. Search for Related Content PubMed PubMed Citation Articles by Navab, M. Articles by Fogelman, A. M. Related Collections Pathophysiology Lipid and lipoprotein metabolism Mechanism of atherosclerosis/growth factors

(Circulation Research. 2005;97:524.)
© 2005 American Heart Association, Inc.

Molecular Medicine

Oral Small Peptides Render HDL Antiinflammatory in Mice and Monkeys and Reduce Atherosclerosis in ApoE Null Mice

Mohamad Navab, G.M. Anantharamaiah, Srinivasa T. Reddy, Susan Hama, Greg Hough, Joy S. Frank, Victor R. Grijalva, Vannakambadi K. Ganesh, Vinod K. Mishra, Mayakonda N. Palgunachari, Alan M. Fogelman

From the David Geffen School of Medicine at UCLA (M.N., S.T.R., S.H., G.H., J.S.F., V.R.G., A.M.F.), Los Angeles, Calif; and the Department of Medicine (G.M.A., V.K.G., V.K.M., M.N.P.), Atherosclerosis Research Unit, University of Alabama at Birmingham.

Correspondence to Mohamad Navab, Ph.D., Room 47-123 CHS, Division of Cardiology, Department of Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095-1679. E-mail mnavab{at}mednet.ucla.edu

A peptide containing only 4 amino acid residues (KRES) that is too small to form an amphipathic helix, reduced lipoprotein lipid hydroperoxides (LOOH), increased paraoxonase activity, increased plasma HDL-cholesterol levels, rendered HDL antiinflammatory, and reduced atherosclerosis in apoE null mice. KRES was orally effective when synthesized from either L or D-amino acids suggesting that peptide-protein interactions were not required. Remarkably, changing the order of 2 amino acids (from KRES to KERS) resulted in the loss of all biologic activity. Solubility in ethyl acetate and interaction with lipids, as determined by differential scanning calorimetry, indicated significant differences between KRES and KERS. Negative stain electron microscopy showed that KRES formed organized peptide-lipid structures whereas KERS did not. Another tetrapeptide FREL shared many of the physical-chemical properties of KRES and was biologically active in mice and monkeys when synthesized from either L- or D-amino acids. After oral administration KRES and FREL were found associated with HDL whereas KERS was not. We conclude that the ability of peptides to interact with lipids, remove LOOH and activate antioxidant enzymes associated with HDL determines their antiinflammatory and antiatherogenic properties regardless of their ability to form amphipathic helixes.

Key Words: atherosclerosis • lipid hydroperoxides • peptides • high-density lipoprotein

This article has been cited by other articles:

				P. R. Moreno, J. Sanz, and V. Fuster Promoting Mechanisms of Vascular Health: Circulating Progenitor Cells, Angiogenesis, and Reverse Cholesterol Transport J. Am. Coll. Cardiol., June 23, 2009; 53(25): 2315 - 2323. [Abstract] [Full Text] [PDF]

				A. Garg and V. Simha Update on Dyslipidemia J. Clin. Endocrinol. Metab., May 1, 2007; 92(5): 1581 - 1589. [Abstract] [Full Text] [PDF]

				A. Kontush and M. J. Chapman Functionally Defective High-Density Lipoprotein: A New Therapeutic Target at the Crossroads of Dyslipidemia, Inflammation, and Atherosclerosis Pharmacol. Rev., September 1, 2006; 58(3): 342 - 374. [Abstract] [Full Text] [PDF]