Journal
JOURNAL OF CARDIOVASCULAR PHARMACOLOGY
Volume 54, Issue 5, Pages 405-411Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/FJC.0b013e3181bad264
Keywords
apolipoprotein A-I; HDL lipoproteins; gene transfer
Funding
- Spanish Society of Cardiology
- Italian Society of Hypertension
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High levels of high-density lipoprotein (HDL) have protective effects against atherosclerosis and cardiovascular diseases. The postulated mechanism of action for these benefits is an enhanced reverse cholesterol transport, Apolipoprotein A-I (ApoA-I) is the major protein of HDL The clinical benefits of raising ApoA-I/HDL have been clearly established by clinical and epidemiological studies. Despite these observations, there are not very effective pharmacological means for raising HDL. ApoA-I gene delivery by viral vectors seems a promising strategy to raise ApoA-I/HDL levels. Sustained gene expression in animals and humans has been attained using adeno-associated viral (AAV) vectors. The aim of the present study was to determine the efficiency, safety, and biological activity of human ApoA-I intramuscularly delivered using in AAV vector ill mice. AAV serotype 8 vector, encoding for human ApoA-l transgene were administered intraportally and intramuscularly ill ApoA-I-deficient animals. ApoA-I levels were measured every 2 weeks post administration. The effectiveness of the generated HDL was tested ill vitro in cholesterol-loaded macrophages. The administration of the vectors resulted in a significant and sustained increase in ApoA-I and HDL plasma levels for up to 16 weeks at similar extent by both routes of administration. Activity of the generated HDL in removal of cholesterol from cholesterol-loaded macrophages was similar in both groups. Our data suggest that intramuscular AAV8-mediated gene transfer of human ApoA-I results in a significant and maintained increase in ApoA-I and functional HDL.
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