Apolipoprotein A-I and lecithin:cholesterol acyltransferase transfer induce cholesterol unloading in complex...

Area of Science:

• Cardiovascular Biology
• Atherosclerosis Research
• Gene Therapy

Background:

• High-density lipoprotein (HDL) cholesterol and apolipoprotein A-I (apo A-I) levels are inversely linked to ischemic cardiovascular disease incidence.
• Reverse cholesterol transport mediated by HDL is a key atheroprotective mechanism.

Purpose of the Study:

• To investigate if elevated HDL cholesterol, induced by hepatocyte-directed gene transfer of rabbit apo A-I (AdrA-I) or lecithin-cholesterol acyltransferase (LCAT) (AdrLCAT), promotes cholesterol unloading in complex atherosclerotic lesions.
• To assess the impact of AdrA-I and AdrLCAT on atherosclerosis progression in a rabbit model.

Main Methods:

• Adenoviral vectors encoding rabbit apo A-I or LCAT were transferred to rabbits with established atherosclerotic lesions.
• Rabbits were fed a cholesterol-rich diet for 420 days before and 120 days after gene transfer.
• HDL cholesterol, non-HDL cholesterol, intima/media ratio, and lesion lipid content (Oil Red O area) were quantified.

Main Results:

• AdrA-I and AdrLCAT transfer significantly increased HDL cholesterol levels (2.0-fold and 1.9-fold, respectively) without altering non-HDL cholesterol.
• A significant reduction in the intima/media ratio (31%) was observed in treated groups compared to controls.
• Treated groups showed a significant reduction in lesion lipid content (1.6-fold for AdrA-I, 1.4-fold for AdrLCAT) compared to baseline.

Conclusions:

• Elevated HDL cholesterol following AdrA-I and AdrLCAT gene transfer effectively inhibits atherosclerosis progression in rabbits.
• Induced HDL cholesterol promotes cholesterol unloading from complex atherosclerotic lesions.
• This study highlights the therapeutic potential of increasing HDL cholesterol for managing atherosclerosis.