Gene transfer of a broad spectrum CC-chemokine inhibitor reduces vein graft atherosclerosis in apolipoprotein E-knockout mice.
BACKGROUND
Accelerated atherosclerosis is a major cause of vein graft failure after bypass surgery. Several CC-chemokines (CC-CKs) mediate monocyte/macrophage recruitment in native atherosclerotic plaques; we hypothesized that CC-CKs may be critical in the development of accelerated atherosclerosis in vein grafts.


RESULTS
Using in vivo gene transfer, we administered a soluble CC-CK binding protein ("35K") to apolipoprotein E-knockout (ApoE-/-) mice that underwent interposition bypass grafting of the vena cava from isogenic donor mice to the common carotid artery. Two days before operation, a recombinant adenovirus encoding either 35K (Ad35K) or green fluorescent protein (AdGFP; control) was injected into recipient mice via the tail vein. 35K greatly reduced CC-CK activity in mouse plasma. After 14 days, vein graft atherosclerotic lesion area, smooth muscle alpha-actin-positive neointimal area, and total vessel wall thickness were strikingly reduced by Ad35K gene transfer compared with AdGFP controls. Furthermore, 35K gene transfer dramatically reduced macrophage content by approximately 90% and cell proliferation by 95%. After 28 days, lesion area and vessel wall thickness remained significantly less in Ad35K mice.


CONCLUSIONS
A single intravenous injection of the CC-CK inhibitor 35K significantly reduced atherosclerosis in carotid-caval vein grafts in ApoE-/- mice. This study highlights the importance of the CC-CK class in accelerated atherosclerosis, and its role as a potential target for improving vein graft patency.
Ali
Ziad A
ZA
Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, United Kingdom.
Bursill
Christina A
CA
Hu
Yanhua
Y
Choudhury
Robin P
RP
Xu
Qingbo
Q
Greaves
David R
DR
Channon
Keith M
KM
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000209:etiology / Q000517:prevention & control*; D001807:Blood Vessel Prosthesis; D017536:Carotid Artery, Common / Q000601:surgery; D002455:Cell Division; D002465:Cell Movement; D019742:Chemokines, CC / Q000037:antagonists & inhibitors*; D017930:Genes, Reporter; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000627:therapeutic use; D006083:Graft Occlusion, Vascular / Q000209:etiology / Q000517:prevention & control*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006937:Hypercholesterolemia / Q000150:complications / Q000235:genetics; D007275:Injections, Intravenous; D008264:Macrophages / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000502:physiology; D012008:Recurrence; D014161:Transduction, Genetic; D014616:Vaccinia virus / Q000235:genetics; D014682:Vena Cava, Inferior / Q000473:pathology* / Q000637:transplantation; 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; D049452:Green Fluorescent Proteins