Abstract 281: Nogo-B, a Novel Regulator of Macrophage Foam Cell Formation

Abstract

Nogo-B, a novel regulator of macrophage foam cell formation Macrophage-derived foam cell formation has long been considered a requisite and initiating event in the development and progression of atherosclerosis. Nogo-B belongs to the reticulon family of proteins and plays important roles in vascular remodeling and angiogenesis in vivo . Previously, we have shown that Nogo -/- mice on an ApoE -/- background develop larger atherosclerotic lesions and increased lipid content compared to ApoE -/- mice in vivo . In the present study, we will define the role of Nogo-B in foam cell formation and its underlying mechanisms. Our results show that both a high-fat regiment and modified LDL stimulation upregulate Nogo-B in macrophages in vivo and in culture, respectively. Loss of Nogo in macrophages increased cholesterol binding, uptake and foam cell formation. Moreover, the loss of Nogo-B specifically increased the expression of type I scavenger receptor A (SR-AI) in modified LDL treated macrophages and in the laser capture microdissected macrophages from atherosclerotic lesions in vivo . Mechanistically, we show that Nogo-B directly binds to MEKK3, and loss of Nogo-B enhanced JNK2 phosphorylation and its downstream c-Jun/AP-1 phosphorylation and nuclear translocation. ChIP assays show c-Jun/AP-1 directly binds to the AP-1 binding sites in the promoter region of Nogo-B and SR-AI and promotes transcription of Nogo-B and SR-AI. Collectively, we have identified Nogo-B as a novel regulator of foam cell formation. Our results suggest that 1) modified LDL activates MEKK3/JNK2/c-Jun signaling pathway, and c-Jun directly activates Nogo-B and SR-AI; 2) upregulated Nogo-B interacts MEKK3 and modulate foam cell formation through negative feedback on the MEKK3/JNK2 pathway.