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CX3CL1-Fc treatment prevents atherosclerosis in Ldlr KO mice
- Riopel, Matthew;
- Vassallo, Melanie;
- Ehinger, Erik;
- Pattison, Jennifer;
- Bowden, Karen;
- Winkels, Holger;
- Wilson, Maria;
- de Jong, Ron;
- Patel, Sanjay;
- Balakrishna, Deepika;
- Bilakovics, James;
- Fanjul, Andrea;
- Plonowski, Artur;
- Larson, Christopher J;
- Ley, Klaus;
- Cabrales, Pedro;
- Witztum, Joseph L;
- Olefsky, Jerrold M;
- Lee, Yun Sok
- et al.
Published Web Location
https://doi.org/10.1016/j.molmet.2018.11.011Abstract
Objective
Atherosclerosis is a major cause of cardiovascular disease. Monocyte-endothelial cell interactions are partly mediated by expression of monocyte CX3CR1 and endothelial cell fractalkine (CX3CL1). Interrupting the interaction between this ligand-receptor pair should reduce monocyte binding to the endothelial wall and reduce atherosclerosis. We sought to reduce atherosclerosis by preventing monocyte-endothelial cell interactions through use of a long-acting CX3CR1 agonist.Methods
In this study, the chemokine domain of CX3CL1 was fused to the mouse Fc region to generate a long-acting soluble form of CX3CL1 suitable for chronic studies. CX3CL1-Fc or saline was injected twice a week (30 mg/kg) for 4 months into Ldlr knockout (KO) mice on an atherogenic western diet.Results
CX3CL1-Fc-treated Ldlr KO mice showed decreased en face aortic lesion surface area and reduced aortic root lesion size with decreased necrotic core area. Flow cytometry analyses of CX3CL1-Fc-treated aortic wall cell digests revealed a decrease in M1-like polarized macrophages and T cells. Moreover, CX3CL1-Fc administration reduced diet-induced atherosclerosis after switching from an atherogenic to a normal chow diet. In vitro monocyte adhesion studies revealed that CX3CL1-Fc treatment caused fewer monocytes to adhere to a human umbilical vein endothelial cell monolayer. Furthermore, a dorsal window chamber model demonstrated that CX3CL1-Fc treatment decreased in vivo leukocyte adhesion and rolling in live capillaries after short-term ischemia-reperfusion.Conclusion
These results indicate that CX3CL1-Fc can inhibit monocyte/endothelial cell adhesion as well as reduce atherosclerosis.Many UC-authored scholarly publications are freely available on this site because of the UC's open access policies. Let us know how this access is important for you.
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