Abstract 516: Strain-Specific Differences in Transcriptome Regulation by Cholesterol Loading in Macrophages from AKR and DBA/2 ApoE-Deficient Mice
Background: Macrophages are a key cell type in atherogenesis as upon cholesterol loading they become foam cells in the arterial intima that provide the earliest histological evidence of atherosclerosis. Thus, atherosclerosis can be viewed as a disease caused by a combination of elevated cholesterol and inflammation.
Methods and Results: We studied the cholesterol loading response of apoE-/- macrophages from atherosclerosis resistant (AKR) and atherosclerosis susceptible (DBA/2) strains. Bone marrow macrophages (BMM) from male and female mice were treated ex vivo with or without AcLDL and whole genome transcriptome data was obtained using Illumina expression microarrays. Transcriptome data were analyzed in gender-specific and combined manners using the Limma R package. Probe data were fitted to a linear model with strain, gender, and cholesterol loading as additive variables to delineate the strain:loading interaction effect. We identified 790 transcripts with a significant strain:loading interaction effect, suggesting that the response to AcLDL was altered in BMM between the two strains. For example the Cd274 gene was up regulated by cholesterol loading in AKR, while down regulated in DBA/2 (p=1.4E-09). Gene enrichment analysis was performed using the Romer R package. The strain:loading differentially regulated transcripts were found to be significantly enriched in sterol regulatory element binding protein (SREBP)-motif-containing genes, which contain binding sites for the SREBP-1a and SREBP-1c transcription factors within 1000 bp of their transcription start site. Nuclear SREBP was found abundantly only in unloaded cells from both strains. The SREBP-motif-containing geneset was significantly enriched in transcripts that were down-regulated in loaded DBA/2 BMM relative to the other samples. We also identified many SREBP-motif associated genes that were up regulated upon cholesterol loading, suggesting a novel function for SREBP as a transcriptional repressor in unloaded macrophages.
Conclusions: Transcriptome profiling can yield insights into strain differences in cholesterol loading and atherosclerosis susceptibility. The SREBP pathway may be alternatively regulated in atherosclerosis resistant and susceptible strains.
- © 2012 by American Heart Association, Inc.