Published Online
on October 11, 2004

A more recent version of this article appeared on October 19, 2004

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Submitted on June 18, 2004
Revised on July 24, 2004
Accepted on July 29, 2004

Broad-Spectrum CC-Chemokine Blockade by Gene Transfer Inhibits Macrophage Recruitment and Atherosclerotic Plaque Formation in Apolipoprotein E-Knockout Mice

Christina A. Bursill PhD, Robin P. Choudhury MD, Ziad Ali MD, David R. Greaves PhD, and Keith M. Channon MD, FRCP^*

From the Department of Cardiovascular Medicine (C.A.B., R.P.C., Z.A., K.M.C.), University of Oxford, John Radcliffe Hospital, and the Sir William Dunn School of Pathology (C.A.B., D.R.G.), University of Oxford, Oxford, England.

^* To whom correspondence should be addressed. E-mail: keith.channon{at}cardiov.ox.ac.uk.

Background--The CC-chemokines (CKs) recruit monocytes/macrophages to sites of inflammation; several different CC-CKs play a role in the pathogenesis of atherosclerosis. The vaccinia virus expresses a 35-kDa soluble protein (35K) that binds to and inactivates nearly all of the CC-CKs, providing a potentially useful therapeutic strategy for broad-spectrum CC-CK inhibition in atherosclerosis. A recombinant adenovirus encoding soluble 35K (Ad35K) was generated to investigate the effect of 35K gene transfer on atherosclerosis in Western diet-fed apolipoprotein E-knockout (ApoE KO) mice.

Methods and Results--ApoE KO mice received tail-vein injections of phosphate-buffered saline, Ad35K, or control adenovirus AdGFP encoding green fluorescence protein. Two weeks after Ad35K gene transfer, atherosclerotic lesion area was significantly reduced in aortic roots by 55% compared with PBS or AdGFP control mice (P<0.05). Furthermore, 35K gene transfer strikingly reduced the macrophage content in aortic root lesions by 85% (P<0.01) and reduced lipid deposition in descending aortas by more than half (P<0.05). By an in vitro chemotaxis assay, plasma and aortic homogenates from 35K gene transfer mice promoted significantly less CC-CK-induced cell migration than did PBS or AdGFP controls.

Conclusions--These findings show that a single intravenous injection of a recombinant adenovirus encoding the broad-spectrum CC-CK inhibitor 35K can reduce atherosclerosis by inhibiting CC-CK-induced macrophage recruitment in atherosclerotic ApoE KO mice. These experiments suggest that CC-CKs play an important role in atherogenesis and are a rational target for therapeutic intervention.

Key words: gene therapy • inflammation • atherosclerosis • plaque • aorta

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