Bone marrow transplantation shows superior atheroprotective effects of gene therapy with apolipoprotein A-I Milano compared with wild-type apolipoprotein A-I in hyperlipidemic mice.
OBJECTIVE
We tested the hypothesis that gene therapy using apolipoprotein A-I Milano (apoA-IMilano) is more effective than that using wild-type apolipoprotein A-I (apoA-I) in reducing atherosclerosis.


BACKGROUND
Apolipoprotein A-I Milano is a naturally occurring mutant with established antiatherogenic activity; however, its relative antiatherogenic efficacy compared with that of wild-type apoA-I remains unclear.


METHODS
We performed bone marrow transplantation in female double-knockout mice lacking both the apoE and apoA-I genes using male donor mice-derived bone marrow that had been transduced with a retroviral vector alone or retroviral vector expressing wild-type apoA-I or apoA-IMilano gene under the control of macrophage-specific scavenger receptor A promoter. Mice were fed a high-cholesterol diet and killed 24 weeks after transplantation, at which time the extent of aortic atherosclerosis was determined.


RESULTS
Compared with vector control (n = 12), apoA-IMilano gene therapy (n = 15) reduced aortic atherosclerosis by 65% (p < 0.001) and plaque macrophage immunoreactivity by 58% (p < 0.0001), whereas wild-type apoA-I (n = 11) reduced atherosclerosis by 25% (p = 0.1) and plaque macrophage immunoreactivity by 23% (p < 0.05). The apoA-IMilano gene therapy was significantly more effective in reducing atherosclerosis (p < 0.05) and macrophage immunoreactivity (p < 0.001) compared with wild-type apoA-I. The circulating levels of cholesterol, lipoprotein profile, and apoA-IMilano or wild-type apoA-I were comparable among the groups. Apolipoprotein A-I Milano was more effective than wild-type apoA-I in promoting macrophage cholesterol efflux.


CONCLUSIONS
Macrophage-specific expression of the apoA-IMilano gene is more effective than wild-type apoA-I in reducing atherosclerosis and plaque inflammation despite comparable circulating levels of the transgene and lipid profile.
Wang
Lai
L
Atherosclerosis Research Center and the Division of Cardiology, Burns and Allen Research Institute and Department of Medicine, Cedars Sinai Medical Center and David Geffen School of Medicine at UCLA, Los Angeles, California 90048, USA.
Sharifi
Behrooz G
BG
Pan
Theresa
T
Song
Lei
L
Yukht
Ada
A
Shah
Prediman K
PK
D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics* / Q000502:physiology; D050197:Atherosclerosis / Q000235:genetics* / Q000628:therapy*; D016026:Bone Marrow Transplantation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D020869:Gene Expression Profiling; D015316:Genetic Therapy; D005822:Genetic Vectors; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D012190:Retroviridae; D019076:Transgenes
D016632:Apolipoprotein A-I; C080631:apolipoprotein A-I Milano