Abstract
ObjectivesThe 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.MethodsThe 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.ResultsMRL-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).ConclusionIn 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.
Highlights
Atherosclerosis is an inflammatory process that is initiated by endothelial dysfunction leading to an increase in adhesiveness of platelets and lymphocytes to the injured region of the artery[1]
We have previously shown that CX3CR1 knockout mice display a 58% decrease in intimal hyperplasia in a vascular injury model relative to wildtype animals [8]
In order to determine any relationship between the involvement of CX3CR1 and CCR2 in the inflammatory response in this model, we tested the effect of a specific CCR2 antagonist (MRL-677) in CX3CR1 knockout mice
Summary
Atherosclerosis is an inflammatory process that is initiated by endothelial dysfunction leading to an increase in adhesiveness of platelets and lymphocytes to the injured region of the artery[1]. CCR2 deficient animals exhibit a decreased susceptibility to atherosclerosis and decreased intimal hyperplasia following arterial injury[11,12]. These two receptors are differentially expressed in monocyte subsets across species from rodent to man[13]. Arterial injury induces vessel wall inflammation by stimulating platelet adherence, leukocyte recruitment, and vascular smooth muscle cell migration and proliferation. These same cellular responses are the basis of atherosclerosis and restenosis
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