Enhancement of Fas ligand-induced inhibition of neointimal formation in rabbit femoral and iliac arteries by coexpression of p35.
Adenovirus-mediated gene transfer of Fas ligand (FasL) inhibits neointimal formation in balloon-injured rat carotid arteries. Vascular smooth muscle (VSM) cells coexpressing murine FasL and p35, a baculovirus gene that inhibits caspase activity, are not susceptible to FasL-mediated apoptosis in vitro but are capable of inducing apoptosis of VSM cells that do not express p35. We reasoned that coexpression of p35 in FasL-transduced VSM cells in vivo would promote their survival, enhance FasL-induced apoptosis of adjacent VSM cells, and thereby facilitate a greater inhibition of neointimal formation. In balloon-injured rabbit femoral arteries, either Ad2/FasL/p35 or Ad2/FasL was infused into the injured site and withdrawn 20 min later. Both vectors induced a dose-dependent reduction (p < 0.05) of the neointima-to-media ratio when assessed 14 days later. However, Ad2/FasL/p35 exhibited a significantly greater inhibition of neointimal formation than Ad2/FasL. In a more clinically relevant model of restenosis, rabbit iliac arteries were injured with an angioplasty catheter under fluoroscopic guidance. Adenoviral vectors were delivered locally to the injured site over a period of 2 min, using a porous infusion balloon catheter. Twenty-eight days after gene transfer angiographic and histologic assessments indicated a significant (p < 0.05) inhibition of iliac artery lumen stenosis and neointimal formation by Ad2/FasL/p35 (5 x 10(11) particles per artery). The extent of inhibition was comparable to that achieved with Ad2/TK, an adenoviral vector encoding thymidine kinase (5 x 10(11) particles per artery) and coadministration of ganciclovir for 7 days. These data suggest that coexpression of p35 in FasL-transduced VSM cells is more potent at inhibiting neointimal formation and as such represents an improved gene therapy approach for restenosis.
Luo
Z
Z
Genzyme Corporation, 31 New York Avenue, Framingham, MA 01701, USA.
Garron
T
T
Palasis
M
M
Lu
H
H
Belanger
A J
AJ
Scaria
A
A
Vincent
K A
KA
Date
T
T
Akita
G Y
GY
Cheng
S H
SH
Barry
J
J
Gregory
R J
RJ
Jiang
C
C
D000260:Adenoviruses, Human; D000818:Animals; D017209:Apoptosis; D021721:Balloon Occlusion; D023903:Coronary Restenosis / Q000517:prevention & control*; D015853:Cysteine Proteinase Inhibitors; D053222:Fas Ligand Protein; D005263:Femoral Artery / Q000293:injuries* / Q000473:pathology; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D007083:Iliac Artery / Q000293:injuries* / Q000473:pathology; D051034:Inhibitor of Apoptosis Proteins; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D011817:Rabbits; D013937:Thymidine Kinase / Q000235:genetics; D017539:Tunica Intima / Q000473:pathology; D014764:Viral Proteins / Q000235:genetics*
D015853:Cysteine Proteinase Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D051034:Inhibitor of Apoptosis Proteins; D008562:Membrane Glycoproteins; D014764:Viral Proteins; C086430:inhibitor of apoptosis, Nucleopolyhedrovirus; D013937:Thymidine Kinase