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CX3CL1-Fc treatment prevents atherosclerosis in Ldlr KO mice.

  • Author(s): 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.
Abstract

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.

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