Journal
CARDIOVASCULAR DIABETOLOGY
Volume 6, Issue -, Pages -Publisher
BMC
DOI: 10.1186/1475-2840-6-15
Keywords
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Funding
- NHLBI NIH HHS [P01 HL22633, P01 HL59407] Funding Source: Medline
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Background: The atheroprotective effects of systemic delivery of either apolipoprotein A-I (wtApoA-I) or the naturally occurring mutant ApoA-I Milano (ApoA-I-M) have been established in animal and human trials, but direct comparison studies evaluating the phenotype of ApoA-I or ApoAI-Milano knock-in mice or bone marrow transplantated animals with selectively ApoA-I or ApoAI-Milano transduced macrophages give conflicting results regarding the superior performance of either one. We therefore sought to compare the two forms of apoA-I using liver-directed somatic gene transfer in hypercholesterinemic mice - a model which is most adequately mimicking the clinical setting. Methods and results: Vectors based on AAV serotype 8 (AAV2.8) encoding wtApoA-I, ApoA-I-M or green fluorescent protein (GFP) as control were constructed. LDL receptor deficient mice were fed a Western Diet. After 8 weeks the AAV vectors were injected, and 6 weeks later atherosclerotic lesion size was determined by aortic en face analysis. Expression of wtApoA-I reduced progression of atherosclerosis by 32% compared with control (p = 0.02) and of ApoA-I-M by 24% (p = 0.04). There was no significant difference between the two forms of ApoA-I in inhibiting atherosclerosis progression. Conclusion: Liver-directed AAV2.8-mediated gene transfer of wtApoA-I and ApoA-I-M each significantly reduced atherosclerosis progression to a similar extent.
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