Abstract 18763: Macrophage-Specific Deletion of Ccaat/Enhancer Protein Beta (C/ebpβ) in ApoE−/− Mice Attenuates Inflammation, Atherosclerosis, and Foam Cell Formation
Background: Atherosclerosis is now considered an inflammatory disease. C/ebpβ is a nuclear transcription factor that in knockout mice attenuates both genetic and dietary obesity. C/ebpβ also plays an important role in macrophage activation, inflammation, and ER stress; however, a specific role for C/ebpβ in processes underlying atherosclerosis and cardiometabolic risk has not yet been investigated.
Methods and Results: Recipient ApoE−/− mice were irradiated and transplanted with bone marrow from C/ebpβ−/− (C/ebpβ−/−→ApoE−/−) mice and WT (WT→ApoE−/−) mice (control). Mice were fed either a high fat diet (HFD) or a low fat diet for 12 weeks. Glucose tolerance testing revealed an improved glucose clearance in C/ebpβ−/−→ApoE−/− mice compared to WT→ApoE−/− mice on HFD; however, the final body weight was similar between groups. C/ebpβ−/−→ApoE−/− mice on HFD showed significant reduction of pro-inflammatory cytokines Il-6, Tnfα in blood and adipose tissue and was associated with marked reduction of Cd68 and Cd11c mRNA expression compared to WT→ApoE−/− mice. Furthermore, C/ebpβ−/−→ApoE−/− mice also demonstrated increased expression of the anti-inflammatory gene adiponectin and the anti-oxidant gene Sod1 in adipose tissue compared to WT→ApoE−/− mice. Sudan 1V staining in the whole aorta of the C/ebpβ−/−→ApoE−/− mouse showed significantly reduced lesion formation. In vitro studies demonstrated that peritoneal macrophages from C/ebpβ−/− mice exposed to oxLDL have attenuated induction of inflammation and apoptosis. Moreover, in RAW 264.7 macrophage cells, shRNA-mediated silencing of C/ebpβ prevented oxLDL-mediated foam cell formation, induction of pro-inflammatory cytokines, and apoptosis but increased expression of proteins involved in cholesterol efflux and uptake.
Conclusions: Our results demonstrate that C/ebpβ in macrophages plays a crucial role in the regulation of obesity-induced inflammation and atherosclerosis independent of body weight. Furthermore, C/ebpβ expression in macrophage regulates foam cell formation and cholesterol efflux. We conclude that targeting C/ebpβ in the macrophage may hold promise for reducing the obesity-associated lipotoxicity associated with HFD and atherosclerosis.
- © 2010 by American Heart Association, Inc.