doi: 10.1161/01.RES.0000194558.86099.ba
© 2005 American Heart Association, Inc.
Editorials |
An Apolipoprotein A-I Mimetic Works Best in the Presence of Apolipoprotein A-I
From the David Geffen School of Medicine (M.N., A.M.F.) at the University of California, Los Angeles; and the Department of Medicine (G.M.A.), Atherosclerosis Research Unit, University of Alabama, Birmingham.
Correspondence to Mohamad Navab, PhD, Room 47-123 CHS, 10833 Le Conte Avenue, Los Angeles, CA 90095-1679. E-mail mnavab{at}mednet.ucla.edu
See related article, pages 1190–1197
Key Words: atherosclerosis • apolipoprotein A-I • high-density lipoprotein
Ou et al1 report that an apolipoprotein A-I (apoA-I) mimetic peptide, D-4F, reduced wall thickness and improved vasoreactivity in the fascialis artery (internal diameter 180 to 240 µm) in low-density lipoprotein (LDL) receptor–null mice on a Western diet. If the mice also lacked apoA-I, D-4F improved vasoreactivity but it did not reduce wall thickness. The authors concluded that apoA-I or some critical threshold of high-density lipoprotein (HDL)-cholesterol was required for maximum effectiveness of D-4F.1
In previous studies these authors reported that LDL caused endothelial nitric oxide synthase to produce more superoxide anion relative to nitric oxide and the balance between nitric oxide and superoxide anion was restored by the apoA-I mimetic peptide 4F.2 In vivo 4F improved vasoreactivity in LDL receptor null mice fed a Western diet and in a mouse model of sickle cell disease.3 Both of these mouse models were wild-type for apoA-I.3
4F is an 18-aa peptide that has no sequence homology with apoA-I but forms a class A amphipathic helix and mimics the lipid binding properties of apoA-I.4 Oral administration of 4F synthesized from all D-amino acids (D-4F) has been shown to dramatically reduce atherosclerosis in mouse models with wild-type apoA-I.5 Oral D-4F synergized with pravastatin to increase intestinal apoA-I synthesis and increase plasma apoA-I levels and caused lesion regression in old apoE-null mice.6
Oral administration of D-4F to apoE-null or C57BL/6 mice caused the formation of small cholesterol-containing particles with pre-ß mobility that were enriched in apoA-I and paraoxonase activity, rendered HDL antiinflammatory, and promoted reverse cholesterol transport from intraperitoneally injected cholesterol-loaded macrophages.7 Oral D-4F also significantly reduced lipoprotein lipid hydroperoxides (LOOH) except for pre-ß HDL fractions in which apoA-I, paraoxonase activity, and LOOH all increased.7
Oral administration of D-4F to monkeys with wild-type apoA-I decreased lipoprotein-LOOH,8 increased paraoxonase activity,4 caused the formation of pre-ß HDL,4 and rendered HDL antiinflammatory.8 Addition of D-4F to human plasma in vitro at a concentration of 250 ng/mL reduced HDL-LOOH, increased paraoxonase activity, increased apoA-I in pre-ß HDL and rendered HDL antiinflammatory.4 The inflammatory properties of HDL appear to be inversely correlated with the ability of HDL to promote cholesterol efflux from macrophages (ie, antiinflammatory HDL is better able to promote cholesterol efflux).9
Ou et al1 reported that treatment with D-4F reduced the association of myeloperoxidase (MPO) with apoA-I in vivo (but not in vitro) and decreased 3-nitrotyrosine content of apoA-I without altering plasma MPO levels. Nitric oxide–derived oxidants (as measured by nitrotyrosine levels) were significantly higher in patients with coronary heart disease (CHD) than in patients without CHD, and statin therapy significantly reduced nitrotyrosine levels, with a magnitude similar to the reductions in total cholesterol and LDL particle number but independent of alterations in C-reactive protein (CRP).10
ApoA-I in human atheroma and in human serum is a selective target for MPO-catalyzed nitration and chlorination.11 As a result of these oxidative alterations of apoA-I there was a marked decrease in the ability of the modified apoA-I to promote cholesterol efflux from macrophages via the ATP binding cassette (ABC) A1 pathway.11
Specific tyrosine residues in apoA-I were altered by MPO-mediated nitration and chlorination and resulted in decreased lipid binding and a decrease in ABCA1-dependent cholesterol efflux from macrophages.12 However, recombinant apoA-I without tyrosine residues was equally susceptible to dose-dependent MPO-mediated loss of ABCA1-dependent cholesterol acceptor activity and loss of lipid binding activity, indicating that nitro- and chlorotyrosine residues were a marker of MPO modification of apoA-I but were not responsible for the loss of function.13
Tyrosine modification in human atherosclerotic intima was 6-fold higher than in circulating HDL and MPO epitopes colocalized with nitrotyrosine.14 HDL from CHD patients contained twice as much 3-nitrotyrosine as did HDL from healthy subjects.14 MPO was identified as a component of lesion HDL, suggesting that MPO and HDL directly interact in atherosclerotic lesions.15
Because D-4F treatment restored vasodilation in both the presence and absence of apoA-I but failed to render HDL antiinflammatory and failed to reduce the thickness of the fascialis artery in the absence of apoA-I, it was concluded that either the presence of apoA-I or some critical level of HDL-cholesterol was required for D-4F to reduce vessel wall thickness.1 The work of Moore et al16 indicates that apoA-I inhibits atherosclerosis by promoting macrophage reverse cholesterol transport and HDL antiinflammatory function independent of HDL-cholesterol levels, and thus suggests that the absence of apoA-I was responsible for the findings of Ou et al with regard to vessel wall thickness and HDL inflammatory properties.1 The ability of D-4F to restore the balance between nitric oxide and superoxide anion production and restore vasoreactivity in the absence of apoA-I suggests that different mechanisms may be involved.
Both native apoA-I and 4F have been reported to have multiple antiinflammatory effects.17 Kruger et al18 reported that D-4F induced vascular heme oxygenase-1 and extracellular superoxide dismutase resulting in decreased endothelial cell sloughing with improved vascular reactivity in a rat model of diabetes. Gupta et al19 recently reported that 4F (but not scrambled 4F) inhibited the inflammatory responses of endothelial cells exposed to bacterial lipopolysaccharide (LPS) or lipid A (the major lipid component of LPS) by reducing LPS binding to its plasma carrier molecule and to endothelial cells.19 Van Lenten et al20 found that D-4F treatment of LDL receptor null mice nasally infected with influenza A virus resulted in decreased lung viral titers, inflammation, and cytokine expression, and decreased macrophage traffic into arteries. D-4F treatment of human type II pneumocytes infected with influenza A virus in vitro reduced viral titers and reduced the secretion of proinflammatory oxidized phospholipids without altering the secretion of nonoxidized phospholipids.21 Caspase activation and cytokine secretion were also dramatically reduced by D-4F treatment.21
Thus, both 4F and native apoA-I have multiple antiinflammatory properties. Because D-4F is not likely to interact with mammalian proteins, its various activities are likely dependent on its lipid binding properties. The demonstration by Ou et al1 that native apoA-I is required for some of its biologic actions is fascinating and presents new opportunities for understanding the mechanism of action of both native apoA-I and apoA-I mimetic peptides.
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Acknowledgments |
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This work was supported by National Institutes of Health grants HL-30568 (to A.M.F.) and HL-34343 (to G.M.A.).
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
M.N., G.M.A., and A.M.F. are principals in Bruin Pharma.
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References |
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 Top References |
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- Ou J, Wang J, Xu H, Ou Z, Sorci-Thomas MG, Jones DW, Signorino P, Densomre JC, Kaus S, Oldham KT, Pritchard KA Jr. Effects of D-4F on vasodilation and vessel wall thickness in hypercholesterolemic LDL receptor null and LDL receptor/ApoA-I double knockout mice on western diet. Circ Res. 2005; 97: 1190–1197.
[Abstract/Free Full Text] - Ou Z, Ou J, Ackerman WA, Oldham KT, Pritchard KA. L-4F, an apolipoprotein A-1 mimetic, restores nitric oxide and superoxide anion balance in low density lipoprotein-treated endothelial cells. Circulation. 2003; 107: 1520–1524.
[Abstract/Free Full Text] - Ou J, Ou Z, Jones DW, Holzhauer S, Hatoum OA, Ackerman AW, Weihrauch DW, Gutterman DD, Guice K, Oldham KT, Hillery CA, Pritchard KA. L-4F, an apolipoprotein A-1 mimetic dramatically improves vasodilation in hypercholesterolemic and sickle cell disease. Circulation. 2003; 107: 2337–2341.
[Abstract/Free Full Text] - Navab M, Anantharamaiah GM, Reddy ST, Hama S, Hough G, Grijalva VR, Yu N, Ansell BJ, Datta G, Garber DW, Fogelman AM. Apolipoprotein A-I mimetic peptides. Arterioscler Thromb Vasc Biol. 2005; 25: 1325–1331.
[Abstract/Free Full Text] - Navab M, Anantharamaiah GM, Hama S, Garber DW, Chaddha M, Hough G, Lallone R, Fogelman AM. Oral administration of an apoA-I mimetic peptide synthesized from D-amino acids dramatically reduces atherosclerosis in mice independent of plasma cholesterol. Circulation. 2002; 105: 290–292.
[Abstract/Free Full Text] - Navab M, Anantharamaiah GM, Hama S, Hough G, Reddy ST, Frank JS, Garber DW, Handattu S, Fogelman AM. D-4F and statins synergize to render HDL anti-inflammatory in mice and monkeys and cause lesion regression in old apolipoprotein E-null mice. Arterioscler Thromb Vasc Biol. 2005; 25: 1426–1432.
[Abstract/Free Full Text] - Navab M, Anantharamaiah GM, Reddy ST, Hama S, Hough G, Grijalva VR, Wagner AC, Frank JS, Datta G, Garber D, Fogelman AM. Oral D-4F causes formation of pre-ß high-density lipoprotein and improves high-density lipoprotein-mediated cholesterol efflux and reverse cholesterol transport from macrophages in apolipoprotein E-null mice. Circulation. 2004; 109: r120–r125.[CrossRef]
- Navab M, Anantharamaiah GM, Reddy ST, Van Lenten BJ, Ansell BJ, Fonarow GC, Vahabzadeh K, Hama S, Hough G, Kamranpour N, Berliner JA, Lusis AJ, Fogelman AM. The oxidation hypothesis of atherogenesis: the role of oxidized phospholipids and HDL. J Lipid Res. 2004; 45: 993–1007.
[Abstract/Free Full Text] - Navab M, Anantharamaiah GM, Reddy ST, Van Lenten BJ, Ansell BJ, Hama S, Hough G, Bachini E, Grijalva VR, Wagner AC, Shaposhnik Z, Fogelman AM. The double jeopardy of HDL. Annals of Medicine. 2005; 37: 173–178.[CrossRef][Medline] [Order article via Infotrieve]
- Shishehbor MH, Aviles RJ, Brennan M-L, Fu X, Goormastic M, Pearce GL, Gokce N, Keaney JF Jr, Penn MS, Sprecher DL, Vita JA, Hazen SL. Association of nitrotyrosine levels with cardiovascular disease and modulation by statin therapy. J Am Med Assoc. 2003; 289: 1675–1680.
[Abstract/Free Full Text] - Zheng L, Nukuna B, Brennan M-L, Sun M, Goormastic M, Settle M, Schmitt D, Fu X, Thomson L, Fox PL, Ischiropoulos H, Smith JD, Kinter M, Hazen SL. Apolipoprotein A-I is a selective target for myeloperoxidase-catalyzed oxidation and functional impairment in subjects with cardiovascular disease. J Clin Invest. 2004; 114: 529–541.[CrossRef][Medline] [Order article via Infotrieve]
- Zheng L, Settle M, Brubaker G, Schmitt D, Hazen SL, Smith JD, Kinter M. Localization of nitration and chlorination sites on apolipoprotein A-I catalyzed by myeloperoxidase in human atheroma and associated oxidative impairment in ABCA1-dependent cholesterol efflux from macrophages. J Biol Chem. 2005; 280: 38–47.
[Abstract/Free Full Text] - Peng D-Q, Wu Z, Brubaker G, Zheng L, Settle M, Gross E, Kinter M, Hazen SL, Smith JD. Tyrosine modification is not required for myeloperoxidase-induced loss of apolipoprotein A-I functional activities. J Biol Chem. 2005; 280: 33775–33784.
[Abstract/Free Full Text] - Pennathur S, Bergt C, Shao B, Byun J, Kassim SY, Singh P, Green PS, McDonald TO, Brunzell J, Chait A, Oram JF, O’Brien K, Geary RL, Heinecke JW. Human atherosclerotic intima and blood of patients with established coronary artery disease contain high density lipoprotein damaged by reactive nitrogen species. J Biol Chem. 2004; 279: 42977–42983.
[Abstract/Free Full Text] - Bergt C, Pennathur S, Fu X, Byun J, O’Brien K, McDonald TO, Singh P, Anantharamaiah GM, Chait A, Brunzell J, Geary RL, Oram JF, Heinecke JW. The myeloperoxidase product hypochlorous acid oxidizes HDL in the human artery wall and impairs ABCA1-dependent cholesterol transport. Proc Natl Acad Sci U S A. 2004; 101: 13032–13037.
[Abstract/Free Full Text] - Moore RE, Navab M, Millar JS, Zimetti F, Hama S, Rothblat GH, Rader DJ. Increased atherosclerosis in mice lacking apolipoprotein A-I attributable to both impaired reverse cholesterol transport and increased inflammation. Circ Res. 2005; 97: 763–771.
[Abstract/Free Full Text] - Barter PJ, Nicholls S, Rye KA, Anantharamaiah GM, Navab M, Fogelman AM. Antiinflammatory properties of HDL. Circ Res. 2004; 95: 764–772.
[Abstract/Free Full Text] - Kruger AL, Peterson S, Turkseven S, Kaminski PM, Zhange FF, Quan S, Wolin MS, Abraham NG. D-4F induces heme oxygenase-1 and extracellular superoxide dismutase, decreases endothelial cell sloughing, and improves vascular reactivity in rat model of diabetes. Circulation. 2005; 111: 3126–3134.
[Abstract/Free Full Text] - Gupta H, Dai L, Datta G, Garber DW, Grenett H, Li Y, Mishra V, Palgunachari MN, Handattu S, Gianturco SH, Bradley WA, Anantharamaiah GM, White CR. Inhibition of lipopolysaccharide-induced inflammatory responses by an apolipoprotein AI mimetic peptide. Circ Res. 2005; 97: 236–243.
[Abstract/Free Full Text] - Van Lenten BJ, Wagner AC, Anantharamaiah GM, Garber DW, Fishbein MC, Adhikary L, Nayak DP, Hama S, Navab M, Fogelman AM. Influenza infection promotes macrophage traffic into arteries of mice that is prevented by D-4F, an apolipoprotein A-I mimetic peptide. Circulation. 2002; 106: 1127–1132.
[Abstract/Free Full Text] - Van Lenten BJ, Wagner AC, Navab M, Anantharamaiah GM, Hui EK-W, Nayak DP, Fogelman AM. D-4F, an apolipoprotein A-I mimetic peptide, inhibits the inflammatory response induced by influenza A infection of human type II pneumocytes. Circulation. 2004; 110: 3252–3258.
[Abstract/Free Full Text]
Related Article:
- 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, and Kirkwood A. Pritchard, Jr
Circ. Res. 2005 97: 1190-1197.[Abstract] [Full Text] [PDF]
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