doi: 10.1161/hc2501.092494
(Circulation. 2001;103:3047.)
© 2001 American Heart Association, Inc.
Brief Rapid Communications |
High-Dose Recombinant Apolipoprotein A-IMilano Mobilizes Tissue Cholesterol and Rapidly Reduces Plaque Lipid and Macrophage Content in Apolipoprotein E–Deficient Mice
Potential Implications for Acute Plaque Stabilization
From the Atherosclerosis Research Center, the Division of Cardiology, Cedars-Sinai Medical Center and UCLA School of Medicine, Los Angeles, Calif and Esperion Therapeutics Inc, Ann Arbor, Mich (C.L.B., S.D.).
Correspondence to Prediman K. Shah, MD, Cedars-Sinai Medical Center, Room # 5347, 8700 Beverly Boulevard, Los Angeles, CA 90048. E-mail shahp{at}cshs.org
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionReferences |
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Background—Repeated doses of recombinant apolipoprotein A-IMilano phospholipid complex (apoA-Im) reduce atherosclerosis and favorably change plaque composition in rabbits and mice. In this study, we tested whether a single high dose of recombinant apoA-Im could rapidly mobilize tissue cholesterol and reduce plaque lipid and macrophage content in apoE-deficient mice.
Methods and Results—High cholesterol–fed, 26-week-old apoE-deficient mice received a single intravenous injection of saline (n=16), 1080 mg/kg dipalmitoylphosphatidylcholine (DPPC; n=14), or 400 mg/kg of recombinant apoA-Im complexed with DPPC (1:2.7 weight ratio; n=18). Blood was sampled before and 1 and 48 hours after injection, and aortic root plaques were evaluated for lipid content and macrophage content after oil-red O and immunostaining, respectively. One hour after injection, the plasma cholesterol efflux–promoting capacity was nearly 2-fold higher in recombinant apoA-Im–treated mice compared with saline and DPPC-treated mice (P<0.01). Compared with baseline values, serum free cholesterol, an index of tissue cholesterol mobilization, increased 1.6-fold by 1 hour after recombinant apoA-Im injection, and it remained significantly elevated at 48 hours (P<0.01). Mice receiving recombinant apoA-Im had 40% to 50% lower lipid content (P<0.01) and 29% to 36% lower macrophage content (P<0.05) in their plaques compared with the saline- and DPPC-treated mice, respectively.
Conclusions—A single high dose of recombinant apoA-Im rapidly mobilizes tissue cholesterol and reduces plaque lipid and macrophage content in apoE-deficient mice. These findings suggest that this strategy could rapidly change plaque composition toward a more stable phenotype.
Key Words: apolipoproteins • cholesterol • atherosclerosis
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Apolipoprotein A-IMilano (apoA-Im) is a naturally occurring mutant of apoA-I, with a cysteine to arginine substitution at position 173, that is associated with freedom from vascular disease and longevity in its carriers, despite markedly reduced HDL and elevated triglyceride levels.1 We have previously demonstrated that repeated administration of recombinant apoA-IMilano complexed with dipalmitoylphosphatidylcholine (DPPC) significantly reduces neointimal lesions in the balloon-injured ileofemoral arteries of cholesterol-fed rabbits and reduces atherosclerosis progression, plaque lipid content, and inflammation in apoE-deficient mice.2 3 Similar results have also been reported by Soma et al4 using a periadventitial carotid injury model in cholesterol-fed rabbits. In the present study, we assessed whether a large single dose of recombinant apoA-Im could rapidly mobilize tissue cholesterol and reduce lipid and macrophage contents in aortic atherosclerotic plaques in apoE-deficient mice.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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ApoE-deficient mice (C57BL/6J strain; age, 5 weeks; weight, 18 to 20 g) obtained from Jackson Laboratory (Bar Harbor, Maine) were fed a high-fat, high-cholesterol (atherogenic) diet containing 21% (wt/wt) fat and 0.15% cholesterol throughout the duration of the experiment. At 26 weeks of age, mice were given a single intravenous injection of 0.5 mL of saline (n=16), 1080 mg/kg of DPPC hydrated in saline (n= 14), or 400 mg/kg of recombinant apoA-Im complexed with DPPC in a protein-to-phospholipid ratio of 1:2.7 by weight and dissolved in 0.5 mL saline (n=18) through the tail vein. All research involving these animals was approved by the Institutional Animal Care and Use Committee and conformed to the Guiding Principles in the Care and Use of Laboratory Animals established by the council of the American Physiology Society. Blood samples were taken before and 1 and 48 hours after injection in EDTA-treated microtainer tubes (Becton Dickinson) and stored at -70°C until analysis. Mice were euthanized 48 hours after injection. Total and free cholesterol levels were measured by enzymatic techniques, and fractional analysis of lipoproteins was performed by online high-performance gel-filtration chromatography. Cholesterol efflux–promoting capacity was determined in the serum 1 hour after injection using the technique described by de La Llera Moya et al.5 The circulating levels of apoA-Im were determined by ELISA, as previously described3
Tissue Preparation and
Histological Analysis
After anesthesia with enflurane, mice
were euthanized, and their hearts and aortas were perfusion-fixed and
harvested as described
previously.3 The lipid and
macrophage contents of aortic root plaques was measured as
described in detail
elsewhere.3
Statistical Analysis
Data are presented as mean±SD. For group
comparisons, ANOVA was followed by Tukey’s test, with
P
0.05 considered
significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Changes in Cholesterol Efflux–Promoting Capacity
One hour after injection, the cholesterol efflux–promoting capacity of the plasma was nearly 2-fold higher in mice receiving recombinant apoA-Im compared with mice receiving saline or DPPC alone (Table
).
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Circulating Cholesterol and
ApoA-Im Levels
Circulating cholesterol levels before
treatment were similar in the 3 groups. One hour after injection, the
total, free, and esterified cholesterol levels increased
significantly in mice receiving recombinant
apoA-Im, and they remained elevated at 48 hours.
There was no significant change in these levels in mice receiving
saline alone. There was a modest increase in total and free
cholesterol levels at 1 hour after administration of DPPC,
with a return to baseline levels by 48 hours
(Table
).
High-performance gel-filtration chromatography
showed that 1 hour after the administration of recombinant
apoA-Im, the increase in free
cholesterol was associated with the HDL fraction, but by 48
hours, it was associated with LDL and VLDL fractions
(Figure,
A). ApoA-Im levels averaged 477 mg/dL at 1 hour
but dropped to 55 mg/dL at 48 hours.
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Lipid Content in Aortic Sinus Plaque
The lipid content in the aortic sinus plaque was 40%
to 50% less in mice receiving recombinant
apoA-Im compared with mice receiving saline
alone or DPPC alone (P<0.001;
Table
and
Figure,
B).
Macrophage Content in Aortic Sinus
Plaque
The macrophage content was 29% to 36% less in
mice receiving recombinant apoA-Im compared with
mice receiving saline (P<0.05;
Table
and
Figure,
C).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This study demonstrates that a single large dose of recombinant apoA-Im rapidly increases the cholesterol efflux–promoting capacity, mobilizes tissue cholesterol, and reduces plaque lipid and macrophage contents within 48 hours in apoE-deficient mice. Because of the close similarity of lesions at 26 weeks to those of advanced human atherosclerosis, we chose to evaluate the effects of recombinant apoA-Im in this model6
Stimulation of Tissue Cholesterol
Mobilization by ApoA-Im
The favorable effects of HDL and apoA-I have been
attributed, in part, to the promotion of reverse
cholesterol
transport.7 One of the first
steps in reverse cholesterol transport is the mobilization
of free cholesterol from tissues, including the
arterial wall, by nascent phospholipid-rich but
cholesterol-poor apoA-I–containing
lipoproteins.7 According to a
recent model, apoA-I acts as an acceptor and the phospholipid component
of HDL acts as a sink for the mobilized
cholesterol.8
Thus, the complex of recombinant apoA-Im and
DPPC simulates a nascent HDL-like particle with the ability to mobilize
cholesterol from peripheral tissues. A rapid
increase in circulating free cholesterol levels within 1
hour of the administration of recombinant
apoA-Im, which was largely HDL-associated, is
consistent with the stimulation of cholesterol
mobilization from peripheral tissues into the circulating
blood. These observations are further supported by our in vitro
findings showing a significantly higher cholesterol
efflux–promoting capacity in the plasma of mice receiving recombinant
apoA-Im compared with mice receiving saline or
DPPC alone. The association of increased cholesterol levels
with the LDL and VLDL fraction observed at 48 hours after recombinant
apoA-Im injection may be related to the transfer
of mobilized cholesterol to these lipoproteins or enhanced
uptake and secretion of cholesterol from the
liver.
Although we have not analyzed all of the potential tissues from which cholesterol mobilization is stimulated by recombinant apoA-Im, our findings of a significant reduction in lipid content in aortic atheromatous lesions suggests that at least part of the mobilized cholesterol is originating from the vessel wall. Recently, a bolus dose of human HDL was shown to stimulate cholesterol efflux from the heart, skeletal muscle, lung, spleen, and liver but not from the brain in normal mice.9 Accumulation of lipid and its subsequent modification within atherosclerotic plaques is thought to play a major role in the recruitment and retention of inflammatory cells in atherosclerosis, and thus a reduction in the plaque lipid may explain the significant decrease in macrophage immunoreactivity after recombinant apoA-Im administration.10
It is likely that most of the mobilized cholesterol is delivered to the liver because the liver plays an important role in eliminating cholesterol through biliary sterol excretion. Enhanced cholesterol mobilization in normal subjects and increased fecal sterol excretion in hyperlipidemic patients after HDL administration has recently been demonstrated.11 12
In the present study, DPPC alone had a small effect, although phospholipid-liposomes have been shown to regress fatty streaks in rabbits.13 Because enhanced reverse cholesterol transport by phospholipid liposomes is facilitated by HDL, modest effects of DPPC alone may have resulted from the low endogenous HDL levels in apoE-deficient mice in a manner consistent with the proposed model of HDL-mediated cholesterol efflux.8
Potential Limitations
Additional studies are required to determine the
precise sources and the fate of the mobilized cholesterol
and to compare the effects with wild-type apoA-I.
Potential Clinical Implications
Although statin therapy favorably alters plaque
composition, such changes occur after weeks and months of
therapy.14 15 By
rapidly mobilizing vessel wall lipids, recombinant
apoA-Im has the potential to stabilize plaques
in the
short-term.14
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Acknowledgments |
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This study was supported in part by the United Hostesses Charities and the Ralph M. Parson’s Foundation. The recombinant apoA-Im–DPPC complex was a generous gift from Guido Franceshchini, PhD, of the University of Milan. The assistance of Jenny Zhu and Helen Xu is acknowledged.
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Footnotes |
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Drs Bisgaier and Drake are employees of Esperion Therapeutics, Inc, a commercial enterprise involved in developing products to prevent and treat cardiovascular diseases, that makes the apoA-IMilano/DPPC described in the article.
Received March 16, 2001; revision received May 1, 2001; accepted May 1, 2001.
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References |
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M. Navab, G.M. Anantharamaiah, S. T. Reddy, S. Hama, G. Hough, V. R. Grijalva, A. C. Wagner, J. S. Frank, G. Datta, D. Garber, et al. Oral D-4F Causes Formation of Pre-{beta} High-Density Lipoprotein and Improves High-Density Lipoprotein-Mediated Cholesterol Efflux and Reverse Cholesterol Transport From Macrophages in Apolipoprotein E-Null Mice Circulation, June 29, 2004; 109(25): 3215 - 3220. [Abstract] [Full Text] [PDF]
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 G. Datta, R. F. Epand, R. M. Epand, M. Chaddha, M. A. Kirksey, D. W. Garber, S. Lund-Katz, M. C. Phillips, S. Hama, M. Navab, et al. Aromatic Residue Position on the Nonpolar Face of Class A Amphipathic Helical Peptides Determines Biological Activity J. Biol. Chem., June 18, 2004; 279(25): 26509 - 26517. [Abstract] [Full Text] [PDF]
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M. Navab, G. M. Ananthramaiah, S. T. Reddy, B. J. Van Lenten, B. J. Ansell, G. C. Fonarow, K. Vahabzadeh, S. Hama, G. Hough, N. Kamranpour, et al. Thematic review series: The Pathogenesis of Atherosclerosis The oxidation hypothesis of atherogenesis: the role of oxidized phospholipids and HDL J. Lipid Res., June 1, 2004; 45(6): 993 - 1007. [Abstract] [Full Text] [PDF]
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G. Rossoni, M. Gomaraschi, F. Berti, C. R. Sirtori, G. Franceschini, and L. Calabresi Synthetic High-Density Lipoproteins Exert Cardioprotective Effects in Myocardial Ischemia/Reperfusion Injury J. Pharmacol. Exp. Ther., January 1, 2004; 308(1): 79 - 84. [Abstract] [Full Text] [PDF]
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 S. E. Nissen, T. Tsunoda, E. M. Tuzcu, P. Schoenhagen, C. J. Cooper, M. Yasin, G. M. Eaton, M. A. Lauer, W. S. Sheldon, C. L. Grines, et al. Effect of Recombinant ApoA-I Milano on Coronary Atherosclerosis in Patients With Acute Coronary Syndromes: A Randomized Controlled Trial JAMA, November 5, 2003; 290(17): 2292 - 2300. [Abstract] [Full Text] [PDF]
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L. Calabresi, M. Gomaraschi, and G. Franceschini Endothelial Protection by High-Density Lipoproteins: From Bench to Bedside Arterioscler Thromb Vasc Biol, October 1, 2003; 23(10): 1724 - 1731. [Abstract] [Full Text] [PDF]
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D. L. Macdonald, T. L. Terry, L. B. Agellon, P. N. Nation, and G. A. Francis Administration of Tyrosyl Radical-Oxidized HDL Inhibits the Development of Atherosclerosis in Apolipoprotein E-Deficient Mice Arterioscler Thromb Vasc Biol, September 1, 2003; 23(9): 1583 - 1588. [Abstract] [Full Text] [PDF]
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 H. M. Crauwels, C. E. Van Hove, P. Holvoet, A. G. Herman, and H. Bult Plaque-associated endothelial dysfunction in apolipoprotein E-deficient mice on a regular diet. Effect of human apolipoprotein AI Cardiovasc Res, July 1, 2003; 59(1): 189 - 199. [Abstract] [Full Text] [PDF]
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S. Kaul, V. Rukshin, R. Santos, B. Azarbal, C. L. Bisgaier, J. Johansson, V. T. Tsang, K.-Y. Chyu, B. Cercek, J. Mirocha, et al. Intramural Delivery of Recombinant Apolipoprotein A-IMilano/Phospholipid Complex (ETC-216) Inhibits In-Stent Stenosis in Porcine Coronary Arteries Circulation, May 27, 2003; 107(20): 2551 - 2554. [Abstract] [Full Text] [PDF]
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J. Ou, Z. Ou, D. W. Jones, S. Holzhauer, O. A. Hatoum, A. W. Ackerman, D. W. Weihrauch, D. D. Gutterman, K. Guice, K. T. Oldham, et al. L-4F, an Apolipoprotein A-1 Mimetic, Dramatically Improves Vasodilation in Hypercholesterolemia and Sickle Cell Disease Circulation, May 13, 2003; 107(18): 2337 - 2341. [Abstract] [Full Text] [PDF]
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P. K. Shah Mechanisms of plaque vulnerability and rupture J. Am. Coll. Cardiol., February 19, 2003; 41(4_Suppl_S): 15S - 22S. [Abstract] [Full Text] [PDF]
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R. P. Choudhury, V. Fuster, J. J. Badimon, E. A. Fisher, and Z. A. Fayad MRI and Characterization of Atherosclerotic Plaque: Emerging Applications and Molecular Imaging Arterioscler Thromb Vasc Biol, July 1, 2002; 22(7): 1065 - 1074. [Abstract] [Full Text] [PDF]
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G. Chiesa, E. Monteggia, M. Marchesi, P. Lorenzon, M. Laucello, V. Lorusso, C. Di Mario, E. Karvouni, R. S. Newton, C. L. Bisgaier, et al. Recombinant Apolipoprotein A-IMilano Infusion Into Rabbit Carotid Artery Rapidly Removes Lipid From Fatty Streaks Circ. Res., May 17, 2002; 90(9): 974 - 980. [Abstract] [Full Text] [PDF]
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 T. G. Cole, W. L. Nowatzke, C. L. Bisgaier, and B. R. Krause Method-dependent Changes in ""HDL-Cholesterol"" with Recombinant Apolipoprotein A-IMilano Infusion in Healthy Volunteers Clin. Chem., April 1, 2002; 48(4): 680 - 681. [Full Text] [PDF]
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M. Navab, G.M. Anantharamaiah, S. Hama, D. W. Garber, M. Chaddha, G. Hough, R. Lallone, and A. M. Fogelman Oral Administration of an Apo A-I Mimetic Peptide Synthesized From D-Amino Acids Dramatically Reduces Atherosclerosis in Mice Independent of Plasma Cholesterol Circulation, January 22, 2002; 105(3): 290 - 292. [Abstract] [Full Text] [PDF]
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M. Navab, B. J. Van Lenten, S. T. Reddy, and A. M. Fogelman High-Density Lipoprotein and the Dynamics of Atherosclerotic Lesions Circulation, November 13, 2001; 104(20): 2386 - 2387. [Full Text] [PDF]
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J. X. Rong, J. Li, E. D. Reis, R. P. Choudhury, H. M. Dansky, V. I. Elmalem, J. T. Fallon, J. L. Breslow, and E. A. Fisher Elevating High-Density Lipoprotein Cholesterol in Apolipoprotein E-Deficient Mice Remodels Advanced Atherosclerotic Lesions by Decreasing Macrophage and Increasing Smooth Muscle Cell Content Circulation, November 13, 2001; 104(20): 2447 - 2452. [Abstract] [Full Text] [PDF]
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P. K. Shah, S. Kaul, J. Nilsson, and B. Cercek Exploiting the Vascular Protective Effects of High-Density Lipoprotein and its Apolipoproteins: An Idea Whose Time for Testing Is Coming, Part II Circulation, November 13, 2001; 104(20): 2498 - 2502. [Full Text] [PDF]
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