title: Natriuretic factors and nitric oxide suppress plasminogen activator inhibitor-1 expression in vascular smooth muscle cells. Role of cGMP in the regulation of the plasminogen system.
abstract: Increased expression of plasminogen activator inhibitor-1 (PAI-1) has been reported in atherosclerotic and balloon-injured vessels. Little is known regarding the factors and mechanisms that may negatively regulate PAI-1 expression. In this report, the effect of cGMP-coupled vasoactive hormones, including natriuretic factors and nitric oxide, on the regulation of PAI-1 expression in vascular smooth muscle cells was examined. Atrial natriuretic factor 1-28 (ANF) and C-type natriuretic factor-22 (CNP) reduced angiotensin II (Ang II)- and platelet-derived growth factor-stimulated PAI-1 mRNA expression in rat aortic smooth muscle cells by 50% to 70%, with corresponding reductions in PAI-1 protein release. Treatment of human aortic smooth muscle cells with CNP similarly inhibited both platelet-derived growth factor-induced PAI-1 mRNA expression and PAI-1 protein release by 50%. Dose-response studies revealed that the inhibitory effects of CNP and ANF on PAI-1 expression were concentration dependent, with IC50s of approximately 1 nmol/L for both natriuretic peptides. Ang II-stimulated PAI-1 expression was also inhibited by the nitric oxide donor S-nitroso-N-acetylpenicillamine. The membrane-permeant cGMP analogue 8-Br-cGMP reduced Ang II-stimulated PAI-1 expression by 60%, and an inhibitor of soluble guanylyl cyclase (1H-[1,2,4]oxadiazolo[4, 3-a]quinoxalin-1-one) significantly impaired the inhibitory effects of S-nitroso-N-acetylpenicillamine on Ang II-stimulated PAI-1 expression. Studies of PAI-1 mRNA stability in cells treated with actinomycin D showed that ANF did not alter PAI-1 mRNA half-life, suggesting that natriuretic factors reduce PAI-1 transcription. These data show that natriuretic factors and nitric oxide, via a cGMP-dependent mechanism, inhibit PAI-1 synthesis in vascular smooth muscle cells. Thus, cGMP-coupled vasoactive hormones may play an important role in suppressing vascular PAI-1 expression.
authors.affiliation: Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Bouchie
authors.forename: H
authors.initials: H
authors.lastname: Hansen
authors.forename: E P
authors.initials: EP
authors.lastname: Feener
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology*; D002478:Cells, Cultured; D003864:Depression, Chemical; D006207:Half-Life; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D020098:Natriuretic Peptide, C-Type / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D020030:Nitric Oxide Donors; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; C110881:S-nitro-N-acetylpenicillamine; D020098:Natriuretic Peptide, C-Type; D009320:Atrial Natriuretic Factor; D010396:Penicillamine