TY - JOUR
T1 - Dual targeting of CCR2 and CX3CR1 in an arterial injury model of vascular inflammation
AU - Jerath, Maya R.
AU - Liu, Peng
AU - Struthers, Mary
AU - DeMartino, Julie A.
AU - Peng, Roche
AU - Peterson, Laurence B.
AU - Cumiskey, Anne Marie
AU - Yang, Lihu
AU - Rojas, Mauricio
AU - Patel, Dhavalkumar D.
AU - Fong, Alan M.
N1 - Funding Information:
We’d like to thank Kathy Lyons for analysis of MRL-677 drug levels, Hong Jin and Kathleen Sullivan for providing additional information on the affinity of MRL-677 for mouse CCR2 and Mike Forrest for his assistance with the in vivo characterization of MRL-677. This work was partly funded by a grant (5RO1HL077406) from the National Heart Lung and Blood Institute of the NIH.
PY - 2010/9/13
Y1 - 2010/9/13
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=77956495514&partnerID=8YFLogxK
U2 - 10.1186/1477-9560-8-14
DO - 10.1186/1477-9560-8-14
M3 - Article
C2 - 20836883
AN - SCOPUS:77956495514
SN - 1477-9560
VL - 8
JO - Thrombosis Journal
JF - Thrombosis Journal
M1 - 14
ER -