We investigated the mechanism of Endothelin-1 regulation by transforming growth factor-beta1 (TGF-beta1) in bovine pulmonary artery endothelial cells (BPAECs) and in isolated perfused rat lungs. Our data show that TGF-beta1 induces ET-1 gene expression and ET-1 peptide synthesis in BPAECs. The induction of preproET-1 mRNA level was due to de novo transcription, as well as mRNA stabilization, and new protein synthesis was not required for this induction. To investigate the role of cAMP-protein kinase A pathway in TGF-beta1-stimulated-ET-1 induction, we exposed BPAECs to various compounds which modulate this pathway. Dibutyryl-cAMP led to an increase in preproET-1 mRNA and Rp-cAMP abolished the induction of preproET-1 mRNA and ET-1 peptide by TGF-beta1. TGF-beta1 increased cAMP in BPAECs. Dexamethasone up-regulated preproET-1 mRNA expression and ET-1 peptide synthesis under basal and TGF-beta1-stimulated conditions. In isolated perfused rat lungs, TGF-beta1 increased preproET-1 mRNA abundance whereas Rp-cAMP inhibited the TGF-beta1-induced ET-1 gene activation. Thus our data suggest that TGF-beta1 stimulates ET-1 gene expression in BPAECs and in rat lungs via a cAMP dependent mechanism.
Copyright 2000 Academic Press.