Atherosclerosis in APOE(*)3-Leiden transgenic mice from proliferative to atheromatous stage

Background - This study documents (1) the progression of atherosclerosis along the entire arterial tree in APOE(*)3-Leiden mice after 1, 4, 6, 9, and 12 months of a high-fat/high-cholesterol (HFC) diet and (2) the amount and phenotype of DNA-synthesizing and apoptotic cells in different lesion types after 6 months of HFC diet. Methods and Results - Diet duration was correlated with a craniocaudal progression of lesion development and with an increase in severity of the lesion. Typically, the lesions contained smooth muscle cells, macrophages, and T lymphocytes and were covered by an intact endothelium. Whereas DNA synthesis (BrdU uptake) was usually elevated in type II lesions (8.6 ± 0.8% versus 1.0 ± 0.2% in the nondiseased arterial wall; P < 0.05), apoptosis was found primarily in advanced lesions (type IV, 1.3 ± 0.1% and type V, 1.2 ± 0.2% versus 0.04 ± 0.04% in the nondiseased arterial wall [P < 0.05]). Cell phenotyping revealed that the majority of DNA synthesis and apoptosis was confined to the macrophage-derived foam cell (68.6 ± 3.0% and 82.2 ± 4.6%, respectively). Conclusions - This study shows that in APOE(*)3-Leiden mice, duration of an HFC diet is associated with (1) a craniocaudal progression of lesion development and (2) an increased complexity of atherosclerotic lesions. Furthermore, DNA synthesis is predominant in early lesions, whereas apoptosis is present mainly in more advanced lesions. Both parameters of cell turnover are confined primarily to the macrophage-derived foam cell.