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Prepublished online as a Blood First Edition Paper on May 31, 2002; DOI 10.1182/blood-2001-12-0251.
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Blood, 1 October 2002, Vol. 100, No. 7, pp. 2487-2493
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Lack of  2-antiplasmin promotes pulmonary heart failure via
overrelease of VEGF after acute myocardial infarction
Hiroyuki Matsuno,
Osamu Kozawa,
Naoki Yoshimi,
Shigeru Akamatsu,
Akira Hara,
Hideki Mori,
Kiyotaka Okada,
Shigeru Ueshima,
Osamu Matsuo, and
Toshihiko Uematsu
From the Departments of Pharmacology and Critical Care
Medicine and the First Department of Pathology, Gifu University School
of Medicine, Gifu, Japan; the First Department of
Pathology, Ryukyu University School of Medicine, Okinawa,
Japan; and the Department of Physiology II, Kinki
University School of Medicine, Osakasayama City, Japan.
Identification of a novel therapy for prevention of sudden death by
ischemic cardiac infarction is an area of intensive investigation. We
here report that the mortality due to an experimental acute myocardial
infarction (AMI) was markedly increased in mice deficient in
 2-antiplasmin (2-AP / mice) but not in mice
deficient in other components acting in fibrinolysis (tissue-type PA,
urokinase type PA, or plasminogen activator inhibitor-1) even if the
infarct area in 2-AP/ mice was not different from
those in the other mice. Echocardiography showed in
2-AP/ mice after AMI an overload of the right
ventricle and that pulmonary permeability was increased. According to
the experiments using explanted myocytes and vascular smooth muscle
cells, it was found that the amount of secreted vascular endothelial
cell growth factor (VEGF) in 2-AP/ mice was markedly
increased compared with that in wild-type mice. Finally, an injection
of an anti-VEGF antibody decreased the mortality after AMI in
2-AP/ mice. Plasmin cleaves extracellular
matrix-bound VEGF to release a diffusible proteolytic fragment and is
inactivated mainly by 2-AP. Therefore, lack of 2-AP could
markedly result in overrelease of VEGF by the continuous activation
of plasmin because of AMI and could result in an acute cor pulmonale.
Our results provide new aspects on the role of 2-AP and VEGF in the
pathogenesis of cardiac events.
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