High-dose recombinant apolipoprotein A-I(milano) mobilizes tissue cholesterol and rapidly reduces plaque lipid and macrophage content in apolipoprotein e-deficient mice. Potential implications for acute plaque stabilization.
BACKGROUND
Repeated doses of recombinant apolipoprotein A-I(Milano) phospholipid complex (apoA-I(m)) reduce atherosclerosis and favorably change plaque composition in rabbits and mice. In this study, we tested whether a single high dose of recombinant apoA-I(m) could rapidly mobilize tissue cholesterol and reduce plaque lipid and macrophage content in apoE-deficient mice.


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-I(m) 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-I(m)-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-I(m) injection, and it remained significantly elevated at 48 hours (P<0.01). Mice receiving recombinant apoA-I(m) 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-I(m) 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.
Shah
P K
PK
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, Michigan, USA. shahp@cshs.org
Yano
J
J
Reyes
O
O
Chyu
K Y
KY
Kaul
S
S
Bisgaier
C L
CL
Drake
S
S
Cercek
B
B
D015060:1,2-Dipalmitoylphosphatidylcholine / Q000494:pharmacology; D000818:Animals; D016632:Apolipoprotein A-I / Q000494:pharmacology*; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001161:Arteriosclerosis / Q000378:metabolism / Q000473:pathology; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D050356:Lipid Metabolism; D008264:Macrophages / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011994:Recombinant Proteins / Q000494:pharmacology; D012850:Sinus of Valsalva / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; D011994:Recombinant Proteins; C080631:apolipoprotein A-I Milano; D015060:1,2-Dipalmitoylphosphatidylcholine; D002784:Cholesterol