Circulation. 2001;103:3047-3050
doi: 10.1161/hc2501.092494
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
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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