From the Departments of Medicine (H.O., T.S., K.M., B.E.S., S.F.) and
Molecular Physiology and Biophysics (J.W.-M., J.M.), The University of
Vermont, College of Medicine (Burlington).
Correspondence to Satoshi Fujii, MD, PhD, The University of Vermont, College of Medicine, B-227 Given Building, Burlington, VT 05405. E-mail sfujii{at}zoo.uvm.edu
Background—Ischemia with or
without reperfusion induces the release of diverse products from
monocytes, including cytokines such as interleukin-1 (IL-1). To
determine whether these phenomena modulate fibrinolysis
and potentially exacerbate impairment of the macrocirculation,
microcirculation, or both, we characterized the effects of IL-1 on the
expression of fibrinolytic system and matrix proteins in rat cardiac
microvascular endothelial cells (CMECs).
Methods and Results—Confluent CMECs were exposed to IL-1 in
serum-free medium for 24 hours, and cell-conditioned medium was assayed
for plasminogen activator inhibitor
type 1 (PAI-1), the primary physiological
inhibitor of plasminogen
activators, and for type 1 collagen with Western blotting.
IL-1 (2 ng/mL) specifically increased the accumulation of PAI-1
(4.4±0.6-fold; mean±SD; n=9) without affecting tissue
plasminogen activator (t-PA) or urokinase
plasminogen activator (u-PA) levels, which
remained unchanged. IL-1 increased the accumulation of collagen in
conditioned media by 3.5±0.7-fold (n=6). Conversely, the accumulation
of both PAI-1 and collagen induced by IL-1 was inhibited with an IL-1
receptor antagonist (200 ng/mL; n=6) and with cycloheximide
(10 µg/mL; n=6), implying that protein synthesis was a requirement
for the effect. To determine whether the IL-1 effect was mediated by
induction of oxygen-centered free radical production, known to
be induced by IL-1, we exposed the cells to the hydroxyl radical
scavenger tetramethylthiourea (10 mmol/L) and observed abolition
of the IL-1–induced increase in the expression of PAI-1 and collagen
(n=6). Conversely, superoxides (generated with 10 mU/mL xanthine
oxidase plus 0.6 mmol/L hypoxanthine, and 100 µmol/L
hydrogen peroxide) induced the accumulation of PAI-1 and collagen
(n=6). IL-1 (1 µg/kg body wt) and lipopolysaccharide (50
µg/kg body wt) administered in vivo increased PAI-1 protein in rat
hearts as detected with Western blotting and PAI-1
immunostaining of rat heart microvessels, indicating
the effects delineated in vitro were paralleled by effects in
vivo.
Conclusions—These results indicate that IL-1–induced
oxygen-centered free radicals stimulate elaboration of PAI-1 and
collagen by CMECs. Accordingly, microvascularly mediated inhibition of
fibrinolysis may predispose to the persistence of
microvascular thrombi, thereby contributing to impaired
microcirculatory function, the no-reflow phenomenon, and cardiac
dysfunction after ischemia and reperfusion.
© 1998 American Heart Association, Inc.
Basic Science Reports
Induction of Plasminogen Activator Inhibitor Type 1 and Type 1 Collagen Expression in Rat Cardiac Microvascular Endothelial Cells by Interleukin-1 and Its Dependence on Oxygen-Centered Free Radicals
Key Words: endothelium • coronary disease • interleukins • plasminogen activators
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