MODIFICATION OF ALTERNATIVE MESSENGER-RNA SPLICING OF FIBROBLAST GROWTH-FACTOR RECEPTORS IN HUMAN CARDIAC ALLOGRAFTS DURING REJECTION

Accelerated coronary atherosclerosis in cardiac transplants (cardiac a llograft vasculopathy, CAV) is characterized by coronary intimal hyper plasia. Acidic fibroblast growth factor (aFGF) is a potent mitogen for vascular smooth muscle cells and endothelial cells, and its expressio n is increased in cardiac allografts, suggesting it may play a role in the pathogenesis of CAV. The activity of aFGF is dependent on binding to transmembrane receptors. To investigate whether receptors for aFGF are also induced after transplantation, polymerase chain reaction, in ;situ hybridization, and immunohistochemistry were used to analyze exp ression of four receptors for aFGF (FGFR1-FGFR4). Expression of mRNA e ncoding extracellular immunoglobulin-like domains of FGFR1 was increas ed 35-fold in cardiac allografts compared with normal hearts and was p redominantly present in cardiac myocytes and vascular structures. Alte rnatively spliced mRNA that encodes transmembrane forms of FGFR1, whic h contain the signal-transducing tyrosine kinase domains, was induced in allografts during rejection, in infiltrating cells, vascular struct ures, and myocytes. In vitro experiments showed that differential expr ession of FGF receptor isoforms was induced by aFGF, and also by IL-6 and TGF-beta, which are expressed in cardiac allografts during rejecti on. The results show that expression of both aFGF and its receptors is altered in cardiac allografts and suggest that these events are impor tant in the pathogenesis of CAV.