Transforming growth factor-beta1 induces endothelin-1 in a bovine pulmonary artery endothelial cell line and rat lungs via cAMP.
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.
Lee
S D
SD
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Asan Medical Center, College of Medicine Ulsan University, 388-1 Poongnab-dong, Songpa-gu, Seoul, Korea. sdlee@www.amc.seoul.kr
Lee
D S
DS
Chun
Y G
YG
Paik
S H
SH
Kim
W S
WS
Kim
D S
DS
Kim
W D
WD
Tuder
R M
RM
Voelkel
N F
NF
D000818:Animals; D002417:Cattle; D000242:Cyclic AMP / Q000378:metabolism*; D019332:Endothelin-1 / Q000096:biosynthesis*; D004727:Endothelium / Q000166:cytology / Q000502:physiology; D005786:Gene Expression Regulation; D008168:Lung / Q000502:physiology*; D008297:Male; D011651:Pulmonary Artery / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1
D019332:Endothelin-1; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000242:Cyclic AMP