Augmented Atherogenesis in LDL Receptor Deficient Mice Lacking Both Macrophage ABCA1 and ApoEReport as inadecuate




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Aim

ABCA1 protects against atherosclerosis by facilitating cholesterol efflux from macrophage foam cells in the arterial wall to extracellular apolipoprotein apo A-I. In contrast to apoA-I, apoE is secreted by macrophages and can, like apoA-I, induce ABCA1-mediated cholesterol efflux. Yet, the combined effect of macrophage ABCA1 and apoE on lesion development is unexplored.

Methods and Results

LDL receptor knockout KO mice were transplanted with bone marrow from ABCA1-apoE double KO dKO mice, their respective single KO-s, and wild-type WT controls and were challenged with a high-fat-high-cholesterol diet for 9 weeks. In vitro cholesterol efflux experiments showed no differences between ABCA1 KO and dKO macrophages. The serum non-HDL-HDL ratio in dKO transplanted mice was 1.7-fold and 2.4-fold p<0.01 increased compared to WT and ABCA1 KO transplanted mice, respectively. The atherosclerotic lesion area in dKO transplanted animals 650±94×103 µm2, however, was 1.9-fold p<0.01 and 1.6-fold p<0.01 increased compared to single knockouts ABCA1 KO: 341±20×103 µm2; apoE KO: 402±78×103 µm2, respectively and 3.1-fold increased p<0.001 compared to WT 211±20×103 µm2. When normalized for serum cholesterol exposure, macrophage ABCA1 and apoE independently protected against atherosclerotic lesion development p<0.001. Moreover, hepatic expression levels of TNFα and IL-6 were highly induced in dKO transplanted animals 3.0-fold; p<0.05, and 4.3-fold; p<0.001, respectively. In agreement, serum IL-6 levels were also enhanced in ABCA1 KO transplanted mice p<0.05 and even further enhanced in dKO transplanted animals 3.1-fold as compared to ABCA1 KO transplanted animals; p<0.05.

Conclusions

Combined deletion of macrophage ABCA1 and apoE results in a defect in cholesterol efflux and, compared to ABCA1 KO transplanted mice, elevated serum total cholesterol levels. Importantly, these mice also suffer from enhanced systemic and hepatic inflammation, together resulting in the observed augmented atherosclerotic lesion development.



Author: Bart Lammers , Ying Zhao, Menno Hoekstra, Reeni B. Hildebrand, Dan Ye, Illiana Meurs, Theo J. C. Van Berkel, Miranda Van Eck

Source: http://plos.srce.hr/



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