Dual targeting of CCR2 and CX3CR1 in an arterial injury model of vascular inflammation

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  • Jerath, Maya R
    • Affiliation: School of Medicine, Department of Medicine
  • Liu, Peng
    • Affiliation: School of Medicine, Department of Medicine
  • Struthers, Mary
    • Other Affiliation: Merck & Co. Rahway, NJ, USA
  • DeMartino, Julie A
    • Other Affiliation: Merck & Co. Rahway, NJ, USA
  • Peng, Roche
    • Other Affiliation: Merck & Co. Rahway, NJ, USA
  • Peterson, Laurence B
    • Other Affiliation: Merck & Co. Rahway, NJ, USA
  • Cumiskey, Anne-Marie
    • Other Affiliation: Merck & Co. Rahway, NJ, USA
  • Yang, Lihu
    • Other Affiliation: Merck & Co. Rahway, NJ, USA
  • Rojas, Mauricio
    • Affiliation: School of Medicine, Department of Medicine
  • Patel, Dhavalkumar D
    • Affiliation: School of Medicine, Department of Medicine
    • Other Affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland
  • Fong, Alan M
    • Affiliation: School of Medicine, Department of Medicine
Abstract
  • Objectives The chemokine receptors CCR2 and CX3CR1 are important in the development of coronary artery disease. The purpose of this study is to analyze the effect of a novel CCR2 inhibitor in conjunction with CX3CR1 deletion on vascular inflammation. Methods The novel CCR2 antagonist MRL-677 was characterized using an in vivo model of monocyte migration. To determine the relative roles of CCR2 and CX3CR1 in vascular remodeling, normal or CX3CR1 deficient mice were treated with MRL-677. After 14 days, the level of intimal hyperplasia in the artery was visualized by paraffin sectioning and histology of the hind limbs. Results MRL-677 is a CCR2 antagonist that is effective in blocking macrophage trafficking in a peritoneal thioglycollate model. Intimal hyperplasia resulting from vascular injury was also assessed in mice. Based on the whole-blood potency of MRL-677, sufficient drug levels were maintained for the entire 14 day experimental period to afford good coverage of mCCR2 with MRL-677. Blocking CCR2 with MRL-677 resulted in a 56% decrease in the vascular injury response (n = 9, p < 0.05) in normal animals. Mice in which both CCR2 and CX3CR1 pathways were targeted (CX3CR1 KO mice given MRL-677) had an 88% decrease in the injury response (n = 6, p = 0.009). Conclusion In this study we have shown that blocking CCR2 with a low molecular weight antagonist ameliorates the inflammatory response to vascular injury. The protective effect of CCR2 blockade is increased in the presence of CX3CR1 deficiency suggesting that CX3CR1 and CCR2 have non-redundant functions in the progression of vascular inflammation.
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  • Article
Rights statement
  • In Copyright
Rights holder
  • Maya R Jerath et al.; licensee BioMed Central Ltd.
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Journal title
  • Thrombosis Journal
Journal volume
  • 8
Journal issue
  • 1
Page start
  • 14
Language
  • English
Is the article or chapter peer-reviewed?
  • Yes
ISSN
  • 1477-9560
Bibliographic citation
  • Thrombosis Journal. 2010 Sep 13;8(1):14
Publisher
  • BioMed Central Ltd
Access right
  • Open Access
Date uploaded
  • August 23, 2012

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