Published Online
on August 12, 2002

A more recent version of this article appeared on September 17, 2002

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Submitted on May 10, 2002
Revised on June 12, 2002
Accepted on June 13, 2002

Overexpression of Soluble Fas Attenuates Transplant Arteriosclerosis in Rat Aortic Allografts

Tao Wang MD, PhD, Chunming Dong MD, Susan C. Stevenson PhD, Edward E. Herderick BA, Jennifer Marshall-Neff BA, Sanjay S. Vasudevan MD, Nicanor I. Moldovan PhD, Robert E. Michler MD, N. Rao Movva PhD, and Pascal J. Goldschmidt-Clermont MD^*

From the Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC (T.W., C.D., S.S.V., P.J.G.C.); Dorothy M. Davis Heart and Lung Research Institute, Department of Biomedical Engineering, The Ohio State University, Columbus, Ohio (E.E.H., N.I.M., R.E.M.); Genetic Therapy, Inc, Gaithersburg, Md (S.C.S., J.M.N.); and the Transplantation Department, Novartis, Basel, Switzerland (N.R.M.).

^* To whom correspondence should be addressed. E-mail: golds017{at}mc.duke.edu.

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) ß-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.

Key words: arteriosclerosis • apoptosis • endothelium • inflammation • gene therapy

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