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(Circulation. 2000;102:III-289.)
© 2000 American Heart Association, Inc.

Myocardial Protection and Vascular Biology

Gene Transfer of the Serine Elastase Inhibitor Elafin Protects Against Vein Graft Degeneration

Stacy B. O’Blenes, MD; Syed H. E. Zaidi, PhD; Alexander Y. L. Cheah, BSc; Brendan McIntyre, BSc; Yasufumi Kaneda, PhD; Marlene Rabinovitch, MD

From the Program in Cardiovascular Research (S.B.O., S.H.E.Z., A.Y.L.C., B.M., M.R.), The Hospital for Sick Children, and Departments of Pediatrics (M.R.), Laboratory Medicine and Pathobiology (S.B.O., S.H.E.Z., M.R.), Medicine (M.R.), and Cardiovascular Surgery (S.B.O.), University of Toronto, Toronto, Ontario, Canada; and Institute for Molecular and Cellular Biology (Y.K.), Osaka University, Osaka, Japan.

Correspondence to Dr Marlene Rabinovitch, Division of Cardiovascular Research, Hospital for Sick Children, 555 University Ave, Toronto, Ontario, Canada M5G 1X8. E-mail mr{at}sickkids.on.ca

Background—Leukocyte infiltration and serine elastase activity lead to smooth muscle cell proliferation in association with posttransplant coronary arteriopathy and may also be involved in vein graft neointimal formation. A number of therapies have targeted cellular proliferation, but the inhibition of serine elastase–mediated extracellular matrix remodeling has not been investigated as a potential strategy to prevent neointimal formation and subsequent atherosclerotic degeneration in vein grafts.

Methods and Results—We studied jugular vein grafts 48 hours after interposition into the carotid arteries of rabbits and demonstrated inflammatory cell infiltration and elevated serine elastase activity, a stimulus for matrix remodeling and deposition of elastin. Therefore, elastolytic activity in vein grafts was targeted through transient expression of the selective serine elastase inhibitor elafin with hemagglutinating virus of Japan liposome–mediated gene transfer. Elafin transfection reduced inflammation by 60% at 48 hours and neointimal formation by 50% at 4 weeks after implantation. At 3 months, a 74% decrease in neointimal elastin deposition correlated with protection against cholesterol-induced macrophage infiltration and lipid accumulation, which were both reduced by 50% in elafin-transfected grafts relative to controls.

Conclusions—Gene transfer of the selective serine elastase inhibitor elafin in vein grafts is effective in reducing the early inflammatory response. Although transient expression of elafin delays neointimal formation, it is also sufficient to cause an alteration in elastin content of the extracellular matrix, making it relatively resistant to atherosclerotic degeneration.

Key Words: atherosclerosis • hypercholesterolemia • leukocytes • plaque • remodeling • genes • elafin