| First Author | Subramanian M | Year | 2015 |
| Journal | Circ Res | Volume | 116 |
| Issue | 2 | Pages | e13-24 |
| PubMed ID | 25348165 | Mgi Jnum | J:249112 |
| Mgi Id | MGI:6098890 | Doi | 10.1161/CIRCRESAHA.116.304794 |
| Citation | Subramanian M, et al. (2015) Identification of a non-growth factor role for GM-CSF in advanced atherosclerosis: promotion of macrophage apoptosis and plaque necrosis through IL-23 signaling. Circ Res 116(2):e13-24 |
| abstractText | RATIONALE: Granulocyte macrophage colony-stimulating factor (GM-CSF, Csf2) is a growth factor for myeloid-lineage cells that has been implicated in the pathogenesis of atherosclerosis and other chronic inflammatory diseases. However, the role of GM-CSF in advanced atherosclerotic plaque progression, the process that gives rise to clinically dangerous plaques, is unknown. OBJECTIVE: To understand the role of GM-CSF in advanced atherosclerotic plaque progression. METHODS AND RESULTS: Ldlr(-/-) mice and Csf2(-/-)Ldlr(-/-) mice were fed a Western-type diet for 12 weeks, and then parameters of advanced plaque progression in the aortic root were quantified. Lesions from the GM-CSF-deficient mice showed a substantial decrease in 2 key hallmarks of advanced atherosclerosis, lesional macrophage apoptosis and plaque necrosis, which indicates that GM-CSF promotes plaque progression. Based on a combination of in vitro and in vivo studies, we show that the mechanism involves GM-CSF-mediated production of interleukin-23, which increases apoptosis susceptibility in macrophages by promoting proteasomal degradation of the cell survival protein Bcl-2 (B-cell lymphoma 2) and by increasing oxidative stress. CONCLUSIONS: In low-density lipoprotein-driven atherosclerosis in mice, GM-CSF promotes advanced plaque progression by increasing macrophage apoptosis susceptibility. This action of GM-CSF is mediated by its interleukin-23-inducing activity rather than its role as a growth factor. |
