(Circulation. 1999;99:2440-2444.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Role of Plasminogen System Components in Focal Cerebral Ischemic Infarction
A Gene Targeting and Gene Transfer Study in Mice
From the Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology (N.N., P.C.), and the Center for Molecular and Vascular Biology (M.D.M., H.R.L., D.C.), KU Leuven, Belgium, and the Department of Physiology, Hamamatsu University School of Medicine, Shizuoka, Japan (N.N.).
Correspondence to Désiré Collen, MD, PhD, Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, KU Leuven, Campus Gasthuisberg, B-3000 Leuven, Belgium. E-mail desire.collen{at}med.kuleuven.ac.be
Background—The role of
plasminogen system components in focal cerebral
ischemic infarction (FCI) was studied in mice deficient in
plasminogen (Plg-/-), in tissue or urokinase
plasminogen activator (tPA-/- or
uPA-/-), or in plasminogen
activator inhibitor-1 or
2-antiplasmin (PAI-1-/- or
2-AP-/-).
Methods and Results—FCI was produced by ligation of the left
middle cerebral artery and measured after 24 hours by planimetry of
stained brain slices. In control (wild-type) mice, infarct size was
7.6±1.1 mm3 (mean±SEM), uPA-/- mice
had similar infarcts (7.8±1.0 mm3,
P=NS), tPA-/- mice smaller (2.6±0.80
mm3, P<0.0001), PAI-1-/- mice
larger (16±0.52 mm3, P<0.0001), and
Plg-/- mice larger (12±1.2 mm3,
P=0.037) infarcts. 2-AP-/-
mice had smaller infarcts (2.2±1.1 mm3,
P<0.0001 versus wild-type), which increased to
13±2.5 mm3 (P<0.005 versus
2-AP-/-) after intravenous
injection of human 2-AP. Injection into
2-AP-/- mice of Fab fragments of
affinospecific rabbit IgG against human 2-AP, after
injection of 200 µg human 2-AP, reduced FCI from
11±1.5 to 5.1±1.1 mm3 (P=0.004).
Conclusions—Plg system components affect FCI at 2 different
levels: (1) reduction of tPA activity (tPA gene
inactivation) reduces whereas its augmentation (PAI-1
gene inactivation) increases infarct size, and (2) reduction of Plg
activity (Plg gene inactivation or 2-AP
injection) increases whereas its augmentation
(2-AP gene inactivation or
2-AP neutralization) reduces infarct size. Inhibition of
2-AP may constitute a potential avenue to treatment
of FCI.
Key Words: plasminogen • plasminogen activators • cerebral infarction • cerebral ischemia
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