Gene transfer of the serine elastase inhibitor elafin protects against vein graft degeneration.
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.


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 approximately 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 approximately 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.
O'Blenes
S B
SB
Program in Cardiovascular Research, The Hospital for Sick Children, Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Zaidi
S H
SH
Cheah
A Y
AY
McIntyre
B
B
Kaneda
Y
Y
Rabinovitch
M
M
D000818:Animals; D001161:Arteriosclerosis / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D002339:Carotid Arteries / Q000601:surgery; D004195:Disease Models, Animal; D004549:Elastin / Q000378:metabolism; D005109:Extracellular Matrix / Q000201:enzymology; D018014:Gene Transfer Techniques; D006083:Graft Occlusion, Vascular / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D007150:Immunohistochemistry; D007601:Jugular Veins / Q000187:drug effects / Q000201:enzymology / Q000637:transplantation*; D008081:Liposomes; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins / Q000008:administration & dosage* / Q000235:genetics* / Q000378:metabolism; D011817:Rabbits; D018108:Respirovirus / Q000235:genetics; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage* / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D017539:Tunica Intima / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D008081:Liposomes; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; D015842:Serine Proteinase Inhibitors; D004549:Elastin