Broad-spectrum CC-chemokine blockade by gene transfer inhibits macrophage recruitment and atherosclerotic plaque formation in apolipoprotein E-knockout mice

Christina A. Bursill, Robin P. Choudhury, Ziad Ali, David R. Greaves, Keith M. Channon

Research output: Contribution to journalArticlepeer-review

61 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2460-2466
Number of pages7
JournalCirculation
Volume110
Issue number16
DOIs
Publication statusPublished or Issued - 19 Oct 2004

Keywords

  • Aorta
  • Atherosclerosis
  • Gene therapy
  • Inflammation
  • Plaque

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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