on August 26, 2004
Published online before print August 26, 2004, doi: 10.1161/01.ATV.0000143135.71440.75
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Submitted on March 1, 2004
Accepted on July 29, 2004
Blockade of Keratinocyte-Derived Chemokine Inhibits Endothelial Recovery and Enhances Plaque Formation After Arterial Injury in ApoE-Deficient Mice
Elisa A. Liehn ;
From the Departments of Molecular Cardiovascular Research (E.A.L., A.S., C.W.) and Cardiology (A.S., C.W.), University Hospital, Rheinisch-Westfälische Technische Hochschule, Aachen, Germany.
* To whom correspondence should be addressed. E-mail: cweber{at}ukaachen.de.
Objective--We evaluated the involvement of keratinocyte-derived chemokine (KC) in neointimal hyperplasia and endothelial repair after arterial injury.
Methods and Results--Expression of KC was detected by immunohistochemistry in carotid arteries of apolipoprotein E-deficient (apoE-/-) mice not earlier than 2 weeks after wire-injury. Double immunofluorescence staining revealed a colocalization of KC with Mac-2-positive macrophages. Immunoreactivity for KC and its receptor CXCR2 was detectable in regenerating CD31-positive endothelial cells. Treatment of apoE-/- mice with a blocking monoclonal antibody (mAb) to KC after carotid injury for 3 weeks substantially increased neointimal plaque area compared with isotype control-treated or untreated mice. As assessed by luminal CD31 or VE-cadherin and Evans blue staining, neutralization of KC inhibited endothelial recovery in injured arteries, whereas macrophage and smooth muscle cell content were unaffected. In vitro, treatment with KC mAb, a blocking CXCR2 mAb, or the CXCR2 antagonist 8-73GRO-
delayed KC-mediated endothelial cell chemotaxis and wound repair of endothelial monolayers after scratch injury. Conversely, addition of exogenous KC accelerated wound repair in a CXCR2-dependent manner.
Conclusions--Neutralization of KC increased plaque formation and delayed endothelial recovery after arterial injury, without affecting neointimal monocyte infiltration. As an underlying mechanism, KC was involved in promoting CXCR2-mediated endothelial chemotaxis and wound repair.
Key words: atherosclerosis • chemokine • restenosis • reendothelialization • injury
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