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Prepublished online as a Blood First Edition Paper on May 31, 2002; DOI 10.1182/blood-2001-12-0251.
Submitted December 14, 2001
Accepted April 11, 2002
Lack of  2-antiplasmin promotes pulmonary heart failure via over-release of VEGF after acute myocardial infarction
Hiroyuki Matsuno, Osamu Kozawa*, Naoki Yoshimi, Sigeru Akamatsu, Akira Hara, Hideki Mori, Kiyotaka Okada, Sigeru Ueshima, Osamu Matsuo, and Toshihiko Uematsu
Department of Pharmacology, Gifu University School of Medicine, Gifu, Japan; Department of Physiology II, Kinki University School of Medicine, Osakasayama City, Japan
Department of Pharmacology, Gifu University School of Medicine, Gifu, Japan
First Department of Pathology, Ryukyu University School of Medicine, Okinawa, Japan
Department of Critical Care Medicine, Gifu University School of Medicine, Gifu, Japan
First Department of Pathology, Gifu University School of Medicine, Gifu, Japan
Department of Physiology II, Kinki University School of Medicine, Osakasayama City, Japan
* Corresponding author; email: okozawa{at}cc.gifu-u.ac.jp.
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 significantly increased in mice deficient in 2-antiplasmin (2-AP-/- mice), but not in mice deficient in other components acting in fibrinolysis (tPA, uPA or PAI-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 over-load of 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 significantly increased as 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 mainly inactivated by 2-AP. Therefore, lack of 2-AP could markedly results in over-release of VEGF by the continuous activation of plasmin due to acute myocardial infarction and results in an acute corpulmonale. Our results provide new aspects on the role of 2-AP and VEGF in the pathogenesis of cardiac events.
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