This Article Full Text Full Text (PDF) All Versions of this Article: 25/7/1426    most recent 01.ATV.0000167412.98221.1av1 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. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Related Collections Lipid and lipoprotein metabolism Mechanism of atherosclerosis/growth factors Pathophysiology

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:1426.)
© 2005 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

D-4F and Statins Synergize to Render HDL Antiinflammatory in Mice and Monkeys and Cause Lesion Regression in Old Apolipoprotein E–Null Mice

Mohamad Navab; G.M. Anantharamaiah; Susan Hama; Greg Hough; Srinivasa T. Reddy; Joy S. Frank; David W. Garber; Shaila Handattu; Alan M. Fogelman

From the From the David Geffen School of Medicine at University of California, Los Angeles (M.N., S.Hama, G.H., S.T.R., J.S.F., A.M.F.), Calif; and the Department of Medicine (G.M.A., D.W.G., S. Handattu), and the Atherosclerosis Research Unit, University of Alabama at Birmingham.

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

Objectives— We tested for synergy between pravastatin and D-4F by administering oral doses of each in combination that were predetermined to be ineffective when given as single agents.

Methods and Results— The combination significantly increased high-density lipoprotein (HDL)–cholesterol levels, apolipoprotein (apo)A-I levels, paraoxonase activity, rendered HDL antiinflammatory, prevented lesion formation in young (79% reduction in en face lesion area; P<0.0001) and caused regression of established lesions in old apoE null mice (ie, mice receiving the combination for 6 months had lesion areas that were smaller than those before the start of treatment (P=0.019 for en face lesion area; P=0.004 for aortic root sinus lesion area). After 6 months of treatment with the combination, en face lesion area was 38% of that in mice maintained on chow alone; P<0.00004) with a 22% reduction in macrophage content in the remaining lesions (P=0.001), indicating an overall reduction in macrophages of 79%. The combination increased intestinal apoA-I synthesis by 60% (P=0.011). In monkeys, the combination also rendered HDL antiinflammatory.

Conclusions— These results suggest that the combination of a statin and an HDL-based therapy may be a particularly potent treatment strategy.

D-4F and pravastatin when given in combination at oral doses that were ineffective when given as single agents rendered HDL antiinflammatory in mice and monkeys and prevented atherosclerosis in young and caused regression of established lesions in old apoE null mice.

Key Words: atherosclerosis • lipoproteins • HDL • apoA-I mimetic peptides • statins

This article has been cited by other articles:

				L. G. Mikael and R. Rozen Homocysteine modulates the effect of simvastatin on expression of ApoA-I and NF-{kappa}B/iNOS Cardiovasc Res, July 1, 2008; (2008) cvn157v2. [Abstract] [Full Text] [PDF]

				E. M. deGoma, R. L. deGoma, and D. J. Rader Beyond high-density lipoprotein cholesterol levels evaluating high-density lipoprotein function as influenced by novel therapeutic approaches. J. Am. Coll. Cardiol., June 10, 2008; 51(23): 2199 - 2211. [Abstract] [Full Text] [PDF]

				B. J. Van Lenten, A. C. Wagner, M. Navab, G. M. Anantharamaiah, S. Hama, S. T. Reddy, and A. M. Fogelman Lipoprotein inflammatory properties and serum amyloid A levels but not cholesterol levels predict lesion area in cholesterol-fed rabbits J. Lipid Res., November 1, 2007; 48(11): 2344 - 2353. [Abstract] [Full Text] [PDF]

				D. Weihrauch, H. Xu, Y. Shi, J. Wang, J. Brien, D. W. Jones, S. Kaul, R. A. Komorowski, M. E. Csuka, K. T. Oldham, et al. Effects of D-4F on vasodilation, oxidative stress, angiostatin, myocardial inflammation, and angiogenic potential in tight-skin mice Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1432 - H1441. [Abstract] [Full Text] [PDF]

				S. J. Peterson, D. Husney, A. L. Kruger, R. Olszanecki, F. Ricci, L. F. Rodella, A. Stacchiotti, R. Rezzani, J. A. McClung, W. S. Aronow, et al. Long-Term Treatment with the Apolipoprotein A1 Mimetic Peptide Increases Antioxidants and Vascular Repair in Type I Diabetic Rats J. Pharmacol. Exp. Ther., August 1, 2007; 322(2): 514 - 520. [Abstract] [Full Text] [PDF]

				S. Zadelaar, R. Kleemann, L. Verschuren, J. de Vries-Van der Weij, J. van der Hoorn, H. M. Princen, and T. Kooistra Mouse Models for Atherosclerosis and Pharmaceutical Modifiers Arterioscler. Thromb. Vasc. Biol., August 1, 2007; 27(8): 1706 - 1721. [Abstract] [Full Text] [PDF]

				M.-D. Wang, R. S. Kiss, V. Franklin, H. M. McBride, S. C. Whitman, and Y. L. Marcel Different cellular traffic of LDL-cholesterol and acetylated LDL-cholesterol leads to distinct reverse cholesterol transport pathways J. Lipid Res., March 1, 2007; 48(3): 633 - 645. [Abstract] [Full Text] [PDF]

				S. P. Handattu, D. W. Garber, D. C. Horn, D. W. Hughes, B. Berno, A. D. Bain, V. K. Mishra, M. N. Palgunachari, G. Datta, G. M. Anantharamaiah, et al. ApoA-I Mimetic Peptides with Differing Ability to Inhibit Atherosclerosis Also Exhibit Differences in Their Interactions with Membrane Bilayers J. Biol. Chem., January 19, 2007; 282(3): 1980 - 1988. [Abstract] [Full Text] [PDF]

				G. M. Buga, J. S. Frank, G. A. Mottino, M. Hendizadeh, A. Hakhamian, J. H. Tillisch, S. T. Reddy, M. Navab, G. M. Anantharamaiah, L. J. Ignarro, et al. D-4F decreases brain arteriole inflammation and improves cognitive performance in LDL receptor-null mice on a Western diet J. Lipid Res., October 1, 2006; 47(10): 2148 - 2160. [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]

				M. Navab, G.M. Anantharamaiah, and A. M. Fogelman An Apolipoprotein A-I Mimetic Works Best in the Presence of Apolipoprotein A-I Circ. Res., November 25, 2005; 97(11): 1085 - 1086. [Full Text] [PDF]

				J. Ou, J. Wang, H. Xu, Z. Ou, M. G. Sorci-Thomas, D. W. Jones, P. Signorino, J. C. Densmore, S. Kaul, K. T. Oldham, et al. 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 Circ. Res., November 25, 2005; 97(11): 1190 - 1197. [Abstract] [Full Text] [PDF]

				M. Navab, G.M. Anantharamaiah, S. T. Reddy, B. J. Van Lenten, A. C. Wagner, S. Hama, G. Hough, E. Bachini, D. W. Garber, V. K. Mishra, et al. An Oral ApoJ Peptide Renders HDL Antiinflammatory in Mice and Monkeys and Dramatically Reduces Atherosclerosis in Apolipoprotein E-Null Mice Arterioscler. Thromb. Vasc. Biol., September 1, 2005; 25(9): 1932 - 1937. [Abstract] [Full Text] [PDF]