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


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.
Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, England.
Christina A
CA
Bursill
Robin P
RP
Choudhury
Ziad
Z
Ali
David R
DR
Greaves
Keith M
KM
Channon
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001018:Aortic Diseases / Q000209:etiology / Q000473:pathology / Q000517:prevention & control / Q000628:therapy; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001161:Arteriosclerosis / Q000209:etiology / Q000473:pathology / Q000517:prevention & control* / Q000628:therapy; D002465:Cell Movement; D019742:Chemokines, CC / Q000037:antagonists & inhibitors / Q000502:physiology*; D002633:Chemotaxis; D004036:Diet, Atherogenic; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000627:therapeutic use*; D006938:Hyperlipoproteinemia Type II / Q000209:etiology / Q000235:genetics; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014161:Transduction, Genetic; D014616:Vaccinia virus / Q000235:genetics; D014764:Viral Proteins / Q000235:genetics / Q000502:physiology*; D037521:Virulence Factors
D001057:Apolipoproteins E; C414049:CCI protein, Cowpox virus; D019742:Chemokines, CC; D011993:Recombinant Fusion Proteins; D014764:Viral Proteins; D037521:Virulence Factors