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Overexpression of ABCG1 protein attenuates arteriosclerosis and endothelial dysfunction in atherosclerotic rabbits
Götz Münch1, Andreas Bültmann, Zhongmin Li
1Corimmun GmbH, (Procorde GmbH) Martinsried, Germany.
Abstract:
The ABCG1 protein is centrally involved in reverse cholesterol transport from the vessel wall. Investigation of the effects of ABCG1 overexpression or knockdown in vivo has produced controversial results and strongly depended on the gene intervention model in which it was studied. Therefore, we investigated the effect of local overexpression of human ABCG1 in a novel model of vessel wall-directed adenoviral gene transfer in atherosclerotic rabbits. We conducted local, vascular-specific gene transfer by adenoviral delivery of human ABCG1 (Ad-ABCG1-GFP) in cholesterol-fed atherosclerotic rabbits in vivo. Endothelial overexpression of ABCG1 markedly reduced atheroprogression (plaque size) and almost blunted vascular inflammation, as shown by markedly reduced macrophage and smooth muscle cell invasion into the vascular wall. Also endothelial function, as determined by vascular ultrasound in vivo, was improved in rabbits after gene transfer with Ad-ABCG1-GFP. Therefore, both earlier and later stages of atherosclerosis were improved in this model of somatic gene transfer into the vessel wall. In contrast to results in transgenic mice, over-expression of ABCG1 by somatic gene transfer to the atherosclerotic vessel wall results in a significant improvement of plaque morphology and composition, and of vascular function in vivo.
Insights
Overexpressing the ABCG1 protein in atherosclerotic rabbits significantly reduced plaque buildup and improved vascular function. This gene therapy approach offers a promising strategy for treating atherosclerosis.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Gene Therapy
Background:
- ABCG1 protein is crucial for reverse cholesterol transport.
- Previous in vivo studies on ABCG1 effects yielded conflicting results.
- Gene intervention models significantly influenced prior findings.
Purpose of the Study:
- To investigate the impact of local ABCG1 overexpression in a novel rabbit atherosclerosis model.
- To assess the therapeutic potential of adenoviral gene transfer targeting the vessel wall.
- To evaluate effects on atheroprogression, vascular inflammation, and endothelial function.
Main Methods:
- Local, vascular-specific gene transfer using adenoviral delivery of human ABCG1 (Ad-ABCG1-GFP).
- Utilized cholesterol-fed atherosclerotic rabbits as the in vivo model.
- Assessed plaque size, vascular inflammation (macrophage/smooth muscle cell invasion), and endothelial function via vascular ultrasound.
Main Results:
- Endothelial ABCG1 overexpression significantly reduced atheroprogression and plaque size.
- Vascular inflammation was markedly blunted, with reduced immune cell infiltration.
- Endothelial function showed significant improvement following Ad-ABCG1-GFP gene transfer.
- Both early and late stages of atherosclerosis were improved.
Conclusions:
- Somatic gene transfer of ABCG1 to the atherosclerotic vessel wall improves plaque morphology and vascular function.
- This approach contrasts with findings in transgenic mice, highlighting model-specific effects.
- Local ABCG1 overexpression demonstrates therapeutic potential for atherosclerosis treatment.
