Circulation, Vol 90, 362-368, Copyright © 1994 by American Heart Association
RT van Leeuwen, A Kol, F Andreotti, C Kluft, A Maseri and G Sperti
BACKGROUND: The role of angiotensin as a vasoconstrictor is well
established. Lately, several other actions of this hormone on vascular
smooth muscle (VSM) cells have been recognized including the induction of
hypertrophy and/or DNA synthesis. Platelet-derived growth factor (PDGF), a
mitogen recently shown to increase plasminogen activator inhibitor type 1
(PAI-1) synthesis in VSM cells, shares with angiotensin II (Ang II) several
steps of its intracellular signaling pathway. METHODS AND RESULTS: The
expression of PAI-1 and tissue-type plasminogen activator (TPA) mRNA in
cultured rat VSM cells was studied. Northern blot analysis demonstrated a
severalfold increase in the PAI-1 mRNA 3 to 8 hours after stimulation with
300 nmol/L Ang II. A similar response for TPA mRNA was observed. This
induction did not require the synthesis of an intermediate protein or
peptide because it was not affected by cycloheximide. In the
cell-conditioned supernatant, the net result was an increase in PAI-1
activity from 4.18 +/- 1.8 to 13.2 +/- 6.8 IU/mL 6 hours after the addition
of 300 nmol/L Ang II (mean +/- SD, P < or = .008, n = 6). The Ang
II-induced increase in PAI activity was dose related, with a maximal effect
at a concentration of 23 nmol/L (n = 3) and an ED50 of 3.3 +/- 1.5 nmol/L
(n = 3). [Sar1-Ile8]angiotensin II, a specific competitive antagonist of
Ang II, blocked 90 +/- 9% (n = 3) of the PAI activity induced by 10 nmol/L
Ang II. In basal conditions, fibrin overlay zymography demonstrated the
presence of free TPA. After stimulation with Ang II, lysis caused by the in
situ dissociation of TPA was also present in the region of the TPA/PAI-1
complex. Angiotensin I (Ang I) elicited an increase in PAI activity similar
to that obtained with equivalent doses of Ang II. Captopril (5
micrograms/mL), an inhibitor of the angiotensin-converting enzyme (ACE),
completely prevented the Ang I effect, demonstrating that VSM cells display
an ACE-like activity. CONCLUSIONS: Recent research has demonstrated the
existence of a localized vascular renin-angiotensin system. The finding
that Ang II can potentially modulate the plasminogen activation in the
arterial wall has important biological and therapeutical implications for
the evolution of arterial wall thrombi and the migration of cells through
the vessel wall in the genesis of atherosclerotic lesions. We speculate
that the reduction in thrombotic events observed in patients with a
previous myocardial infarction and in high-renin, hypertensive patients
treated with ACE inhibitors could be due at least in part to the decreased
production of PAI-1 by VSM cells caused by these agents.
ARTICLES
Angiotensin II increases plasminogen activator inhibitor type 1 and tissue-type plasminogen activator messenger RNA in cultured rat aortic smooth muscle cells
Istituto di Cardiologia, Universita Cattolica Del Sacro Cuore, Rome, Italy.
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