CONFIRMATION OF ALTERNATIVELY SPLICED PLATELET-DERIVED GROWTH FACTOR-A CHAIN AND CORRELATION WITH EXPRESSION OF PDGF RECEPTOR-ALPHA IN HUMAN CARDIAC ALLOGRAFTS

PDGF is a potent mitogen for vascular smooth muscle cells (SMC) and ma y play an important role in the pathogenesis of cardiac allograft vasc ulopathy (CAV), Two isoforms of PDGF-A chain exist as a result of alte rnative mRNA splicing that either includes (long-form) or excludes (sh ort-form) exon 6. Short-form PDGF-A is expressed in both resting and a ctivated cells, while the long-form is present predominantly in activa ted cells, Using RT/PCR, we have found previously that long-form PDGF- A chain was expressed in human cardiac allografts but not in normal hu man hearts. In the experiments reported here, we studied the cellular distribution of PDGF-A chain isoforms and expression of PDGF receptor- alpha in cardiac allografts, In situ hybridization and immunohistochem istry confirmed the PCR data and demonstrated that expression of long- form PDGF-A chain was diffusely increased in cardiac allografts, predo minantly in myocytes and vascular structures, Expression of PDGF recep tor alpha also was induced in cardiac allografts and was not detected in any of the normal hearts, Induction of PDGF receptor alpha in cardi ac allografts was associated with the presence of long-form PDGF-A cha in, In vitro experiments with human endothelial cells demonstrated tha t aFGF, IL-6, and TGF-beta, which are produced in cardiac allografts i n vivo, induced expression of long-form PDGF-A chain, Expression of lo ng-form PDGF-A chain and its receptor was markedly increased in cardia c allografts, predominantly in vascular structures and myocytes, Alter ative splicing of PDGF-A chain variants may be mediated by growth fact ors and cytokines produced in vivo.