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EXPEDITED REVIEW

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

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.

Manuscript received January 27, 2006; revised manuscript received June 19, 2006, accepted July 10, 2006.

^_* Reprint requests and correspondence: Dr. Prediman K. Shah, Division of Cardiology and Atherosclerosis Research Center, Room 5531, Cedars Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048 (Email: Shahp{at}cshs.org).

OBJECTIVES: 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.

Abbreviations and Acronyms   apoA-I = apolipoprotein A-I   apoA-IMilano = apolipoprotein A-I Milano   DPPC = dipalmitoyl phosphatidylcholine   ELISA = enzyme-linked immunosorbent assay   GFP = green fluorescent protein   HDL = high-density lipoprotein   LDL = low-density lipoprotein   PCR = polymerase chain reaction   RT = reverse transcriptase   SR-A = scavenger receptor A

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