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(Circulation. 2005;112:I-235 – I-241.)
© 2005 American Heart Association, Inc.

Myocardial Protection and Vascular Biology

Gene Transfer of a Broad Spectrum CC-Chemokine Inhibitor Reduces Vein Graft Atherosclerosis in Apolipoprotein E–Knockout Mice

Ziad A. Ali, MD; Christina A. Bursill, PhD; Yanhua Hu, MD; Robin P. Choudhury, MD; Qingbo Xu, MD, PhD; David R. Greaves, PhD; Keith M. Channon, MD

From the Department of Cardiovascular Medicine (Z.A.A., C.A.B., R.P.C., K.M.C.), University of Oxford, John Radcliffe Hospital, United Kingdom; Sir William Dunn School of Pathology (Z.A.A., C.A.B., D.R.G.), University of Oxford, United Kingdom; Department of Cardiological Sciences (Y.H., Q.X.), St Georges Hospital Medical School, London, UK.

Correspondence to Professor Keith Channon, Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU. E-mail keith.channon{at}cardiov.ox.ac.uk

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.

Methods and 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 -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 90% and cell proliferation by 95%. After 28 days, lesion area and vessel wall thickness remained significantly less in Ad35K mice.

Conclusion— 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.

Key Words: gene therapy • inflammation • atherosclerosis • veins • surgery