(Circulation. 1999;99:2295-2301.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Prevention of Cardiac Allograft Arteriosclerosis by Protein Tyrosine Kinase Inhibitor Selective for Platelet-Derived Growth Factor Receptor
From the Cardiopulmonary Research Group of the Transplantation Laboratory, University of Helsinki and Helsinki University Central Hospital, and Novartis Pharma, Basel, Switzerland (E.B.).
Correspondence to Karl Lemström, MD, PhD, Cardiopulmonary Research Group of the Transplantation Laboratory, University of Helsinki and Helsinki University Central Hospital, PO Box 21 (Haartmaninkatu 3), FIN-00014 Helsinki, Finland. E-mail karl.lemstrom{at}helsinki.fi
Background—Increased
immunoreactivity of platelet-derived growth factor (PDGF)-AA,
-R
, and -Rß in intimal cells correlates with the development of
cardiac allograft arteriosclerosis, a condition for
which there is little or no current therapy. Therefore, we hypothesized
that PDGF may have a rate-limiting role in the development of this
disease.
Methods and Results—The hypothesis was tested in a rat model of
heterotopic cardiac and aortic allografts using dark agouti (AG-B4,
RT1a) donors and Wistar-Furth (AG-B2,
RT1u) recipients. The recipients received CGP 53716, a
selective PDGF-R protein tyrosine kinase inhibitor, 50
mg · kg-1 · d-1, or vehicle for
60 days. Cardiac allograft recipients also received background
cyclosporin A immunosuppression. Our results demonstrate that CGP 53716
significantly reduced the incidence and intensity of
arteriosclerotic lesions in rat cardiac and aortic
allograft recipients. When rat coronary smooth muscle cells
were stimulated in vitro with PDGF-AA or -BB in the presence of
interleukin-1ß or tumor necrosis factor-, CGP 53716 significantly
inhibited only AA-ligand–induced but not BB-ligand–induced
replication. Concomitantly, in quantitative reverse
transcriptase–polymerase chain reaction, interleukin-1ß or tumor
necrosis factor- stimulation specifically upregulated the expression
of PDGF-R mRNA but not of other ligand or receptor genes in cultured
smooth muscle cells.
Conclusions—We conclude that a PDGF-AA/R–dependent cycle is
induced in the generation of allograft
arteriosclerosis that may be inhibited by blocking
of signaling downstream of PDGF-R.
Key Words: transplantation • muscle, smooth • cells • proteins
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