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

Abstract

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 α-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.