Dual targeting of CCR2 and CX3CR1 in an arterial injury model of vascular inflammation
<p>Abstract</p> <p>Objectives</p> <p>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 inflamm...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2010-09-01
|
| Series: | Thrombosis Journal |
| Online Access: | http://www.thrombosisjournal.com/content/8/1/14 |
| _version_ | 1818140652544720896 |
|---|---|
| author | Jerath Maya R Liu Peng Struthers Mary DeMartino Julie A Peng Roche Peterson Laurence B Cumiskey Anne-Marie Yang Lihu Rojas Mauricio Patel Dhavalkumar D Fong Alan M |
| author_facet | Jerath Maya R Liu Peng Struthers Mary DeMartino Julie A Peng Roche Peterson Laurence B Cumiskey Anne-Marie Yang Lihu Rojas Mauricio Patel Dhavalkumar D Fong Alan M |
| author_sort | Jerath Maya R |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Objectives</p> <p>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.</p> <p>Methods</p> <p>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.</p> <p>Results</p> <p>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).</p> <p>Conclusion</p> <p>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.</p> |
| first_indexed | 2024-12-11T10:47:23Z |
| format | Article |
| id | doaj.art-952cf346159144dda6a6414b6ddf6149 |
| institution | Directory Open Access Journal |
| issn | 1477-9560 |
| language | English |
| last_indexed | 2024-12-11T10:47:23Z |
| publishDate | 2010-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Thrombosis Journal |
| spelling | doaj.art-952cf346159144dda6a6414b6ddf61492022-12-22T01:10:26ZengBMCThrombosis Journal1477-95602010-09-01811410.1186/1477-9560-8-14Dual targeting of CCR2 and CX3CR1 in an arterial injury model of vascular inflammationJerath Maya RLiu PengStruthers MaryDeMartino Julie APeng RochePeterson Laurence BCumiskey Anne-MarieYang LihuRojas MauricioPatel Dhavalkumar DFong Alan M<p>Abstract</p> <p>Objectives</p> <p>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.</p> <p>Methods</p> <p>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.</p> <p>Results</p> <p>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).</p> <p>Conclusion</p> <p>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.</p>http://www.thrombosisjournal.com/content/8/1/14 |
| spellingShingle | Jerath Maya R Liu Peng Struthers Mary DeMartino Julie A Peng Roche Peterson Laurence B Cumiskey Anne-Marie Yang Lihu Rojas Mauricio Patel Dhavalkumar D Fong Alan M Dual targeting of CCR2 and CX3CR1 in an arterial injury model of vascular inflammation Thrombosis Journal |
| title | Dual targeting of CCR2 and CX3CR1 in an arterial injury model of vascular inflammation |
| title_full | Dual targeting of CCR2 and CX3CR1 in an arterial injury model of vascular inflammation |
| title_fullStr | Dual targeting of CCR2 and CX3CR1 in an arterial injury model of vascular inflammation |
| title_full_unstemmed | Dual targeting of CCR2 and CX3CR1 in an arterial injury model of vascular inflammation |
| title_short | Dual targeting of CCR2 and CX3CR1 in an arterial injury model of vascular inflammation |
| title_sort | dual targeting of ccr2 and cx3cr1 in an arterial injury model of vascular inflammation |
| url | http://www.thrombosisjournal.com/content/8/1/14 |
| work_keys_str_mv | AT jerathmayar dualtargetingofccr2andcx3cr1inanarterialinjurymodelofvascularinflammation AT liupeng dualtargetingofccr2andcx3cr1inanarterialinjurymodelofvascularinflammation AT struthersmary dualtargetingofccr2andcx3cr1inanarterialinjurymodelofvascularinflammation AT demartinojuliea dualtargetingofccr2andcx3cr1inanarterialinjurymodelofvascularinflammation AT pengroche dualtargetingofccr2andcx3cr1inanarterialinjurymodelofvascularinflammation AT petersonlaurenceb dualtargetingofccr2andcx3cr1inanarterialinjurymodelofvascularinflammation AT cumiskeyannemarie dualtargetingofccr2andcx3cr1inanarterialinjurymodelofvascularinflammation AT yanglihu dualtargetingofccr2andcx3cr1inanarterialinjurymodelofvascularinflammation AT rojasmauricio dualtargetingofccr2andcx3cr1inanarterialinjurymodelofvascularinflammation AT pateldhavalkumard dualtargetingofccr2andcx3cr1inanarterialinjurymodelofvascularinflammation AT fongalanm dualtargetingofccr2andcx3cr1inanarterialinjurymodelofvascularinflammation |