© 1998 American Heart Association, Inc.
Original Contributions |
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
From the Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Mass.
Correspondence to Edward P. Feener, PhD, Research Division, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. E-mail feenere{at}joslab.harvard.edu
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 
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.
Key Words: natriuretic factors • nitric oxide • plasminogen activator inhibitor • vascular smooth muscle cells • angiotensin II
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