Münch Götz, Bültmann Andreas, Li Zhongmin, Holthoff Hans-Peter, Ullrich Julia, Wagner Silvia, Ungerer Martin
Corimmun GmbH, (Procorde GmbH) Martinsried, Germany.
Heart Int. 2012 Jun 5;7(2):e12. doi: 10.4081/hi.2012.e12. Epub 2012 Jun 25.
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.
ABCG1蛋白在胆固醇从血管壁的逆向转运过程中发挥着核心作用。对ABCG1在体内过表达或敲低的影响进行研究产生了有争议的结果，且很大程度上取决于所采用的基因干预模型。因此，我们在一种新型的针对动脉粥样硬化兔的血管壁定向腺病毒基因转移模型中，研究了人ABCG1局部过表达的影响。我们通过腺病毒介导人ABCG1（Ad-ABCG1-GFP）在体内对喂食胆固醇的动脉粥样硬化兔进行局部、血管特异性基因转移。ABCG1在内皮细胞中的过表达显著减少了动脉粥样硬化进展（斑块大小），并几乎消除了血管炎症，表现为巨噬细胞和平滑肌细胞向血管壁内浸润明显减少。此外，通过体内血管超声测定，基因转移Ad-ABCG1-GFP后的兔内皮功能也得到了改善。因此，在这种向血管壁进行体细胞基因转移的模型中，动脉粥样硬化的早期和晚期阶段均得到了改善。与转基因小鼠的结果相反，通过体细胞基因转移使动脉粥样硬化血管壁过表达ABCG1可显著改善斑块形态和成分以及体内血管功能。
