TY - JOUR
T1 - Overexpression of soluble Fas attenuates transplant arteriosclerosis in rat aortic allografts
AU - Wang, Tao
AU - Dong, Chunming
AU - Stevenson, Susan C.
AU - Herderick, Edward E.
AU - Marshall-Neff, Jennifer
AU - Vasudevan, Sanjay S.
AU - Moldovan, Nicanor I.
AU - Michler, Robert E.
AU - Movva, N. Rao
AU - Goldschmidt-Clermont, Pascal J.
PY - 2002/9/17
Y1 - 2002/9/17
N2 - Background - The killing of vascular cells by activated macrophages is an important step in the process of destabilization of the arterial wall. The death receptor Fas is implicated in vascular cell death. Hence, we extended our studies in a rat aortic allograft model, using adenovirus-mediated overexpression of soluble Fas (sFas) to block Fas binding to Fas ligand (Fas-L). The contribution of Fas to vascular cell injury and consequent transplant arteriosclerosis was investigated. Methods and Results - Activated monocytes in the presence of macrophage colony-stimulating factor induce endothelial cell apoptosis in vitro, which was significantly inhibited by adenovirus-mediated sFas overexpression. Next, donor rat abdominal aortas were either untreated or transduced with adenoviruses encoding (1) rat soluble Fas (Ad3rsFas), (2) no insert (Ad3Null), and (3) β-galactosidase (Ad3nBg). A total of 175 aortic grafts were harvested 2 to 90 days after transplantation. Vascular cell apoptosis and CD45+ cell infiltration were significantly reduced in Ad3rsFas-transduced aortas, as compared with control allografts. Moreover, the control allografts developed marked intimal thickening, whereas Ad3rsFas-transduced allografts had significantly less neointima until the 90-day time point. Conclusions - sFas overexpression protects the integrity of the vessel wall from immune injury and attenuates transplant arteriosclerosis.
AB - Background - The killing of vascular cells by activated macrophages is an important step in the process of destabilization of the arterial wall. The death receptor Fas is implicated in vascular cell death. Hence, we extended our studies in a rat aortic allograft model, using adenovirus-mediated overexpression of soluble Fas (sFas) to block Fas binding to Fas ligand (Fas-L). The contribution of Fas to vascular cell injury and consequent transplant arteriosclerosis was investigated. Methods and Results - Activated monocytes in the presence of macrophage colony-stimulating factor induce endothelial cell apoptosis in vitro, which was significantly inhibited by adenovirus-mediated sFas overexpression. Next, donor rat abdominal aortas were either untreated or transduced with adenoviruses encoding (1) rat soluble Fas (Ad3rsFas), (2) no insert (Ad3Null), and (3) β-galactosidase (Ad3nBg). A total of 175 aortic grafts were harvested 2 to 90 days after transplantation. Vascular cell apoptosis and CD45+ cell infiltration were significantly reduced in Ad3rsFas-transduced aortas, as compared with control allografts. Moreover, the control allografts developed marked intimal thickening, whereas Ad3rsFas-transduced allografts had significantly less neointima until the 90-day time point. Conclusions - sFas overexpression protects the integrity of the vessel wall from immune injury and attenuates transplant arteriosclerosis.
KW - Apoptosis
KW - Arteriosclerosis
KW - Endothelium
KW - Gene therapy
KW - Inflammation
UR - http://www.scopus.com/inward/record.url?scp=0037125952&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0037125952&partnerID=8YFLogxK
U2 - 10.1161/01.CIR.0000027822.23269.07
DO - 10.1161/01.CIR.0000027822.23269.07
M3 - Article
C2 - 12234961
AN - SCOPUS:0037125952
SN - 0009-7322
VL - 106
SP - 1536
EP - 1542
JO - Circulation
JF - Circulation
IS - 12
ER -