Adrenomedullin inhibits angiotensin II-induced expression of tissue factor and plasminogen activator inhibitor-1 in cultured rat aortic endothelial cells.
Adrenomedullin (AM) is a potent vasodilating peptide having a variety of pharmacological properties mainly in respect to vascular pathophysiology. We have previously demonstrated that angiotensin II (Ang II) or natriuretic peptides have influence on the expression of tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) in vascular endothelial cells. The aim of this study was to elucidate the effects of AM on TF and PAI-1 mRNA and protein expression in endothelial cells. As a result, AM inhibited Ang II-induced TF and PAI-1 mRNA expression in a dose- and time-dependent manner. Because the expression of TF and PAI-1 mRNA induced by Ang II was attenuated by the increase of intracellular concentrations of cAMP by forskolin and 8-bromo-cAMP and because AM increased the intracellular level of cAMP in rat aortic endothelial cells, it was indicated that the inhibitory effect of AM on the expressions of TF and PAI-1 was mainly mediated by the cAMP-dependent signal transduction. Furthermore, the inhibitory effect of AM on TF and PAI-1 expression was partly attenuated by an NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester. In conclusion, AM is shown to contribute to the regulation of blood coagulation and fibrinolysis by vascular endothelial cells mainly via the cAMP pathway.
Sugano
T
T
Second Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Tsuji
H
H
Masuda
H
H
Nishimura
H
H
Yoshizumi
M
M
Kawano
H
H
Kimura
S
S
Ukimura
N
N
Yano
S
S
Kunieda
Y
Y
Nakagawa
K
K
Nakagawa
M
M
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D053607:Adrenomedullin; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000166:cytology*; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology*; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013925:Thromboplastin / Q000096:biosynthesis / Q000235:genetics*; D015533:Transcriptional Activation / Q000187:drug effects
D010446:Peptide Fragments; D010455:Peptides; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; C104782:adrenomedullin (22-52); D000804:Angiotensin II; D053607:Adrenomedullin; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D013925:Thromboplastin; D000242:Cyclic AMP