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Blood, 1 April 2004, Vol. 103, No. 7, pp. 2610-2616.
Prepublished online as a Blood First Edition Paper on November 20, 2003; DOI 10.1182/blood-2003-03-0835.
Submitted March 28, 2003
Accepted November 17, 2003
Essential role of endogenous tissue plasminogen activator via matrix metalloproteinase 9 induction and expression on heparin-produced cerebral hemorrhage after cerebral ischemia in mice
Bing-Qiao Zhao, Yasuhiko Ikeda, Hayato Ihara, Tetsumei Urano, WenYing Fan, Sumiko Mikawa, Yasuhiro Suzuki, Kazunao Kondo, Kohji Sato, Nobuo Nagai, and Kazuo Umemura*
Department of Pharmacology, Hamamatsu University School of Medicine, Hamamatsu, Japan
Department of Physiology, Hamamatsu University School of Medicine, Hamamatsu, Japan
Department of Anatomy and Neuroscience, Hamamatsu University School of Medicine, Hamamatsu, Japan
Center for Molecular and Vascular Biology, Leuven University, Leuven, Belgium
* Corresponding author; email: umemura{at}hama-med.ac.jp.
Cerebral hemorrhage associated with antithrombotic and thrombolytic therapy in acute stroke continues to present a major clinical problem. Rupture of cerebral microvasculature involves the degradation and remodeling of extracellular matrix. Here, we demonstrated that delayed administration of heparin 3 hours after photothrombotic middle cerebral artery occlusion (MCAO) caused cerebral hemorrhage in wild-type (WT) mice, but not in tissue plasminogen activator (tPA) deficient (KO) mice. Heparin administration increased tPA activity and its mRNA expression at 6 and 12 hours after MCAO in the ischemic hemisphere of WT mice. The expression of tPA enhanced in microglial cells in the ischemic border zone. We also observed an exacerbation of matrix metalloproteinase (MMP) 9 expression at the mRNA levels and its conversion to an active form following heparin administration in the ischemic hemisphere in WT mice but not in tPA KO mice. The increased MMP 9 expression was localized in microglial cells and endothelial cells. These findings suggest that endogenous tPA, via enhancement of MMP 9 expression and proteolytic activation, plays an essential role in the pathogenesis of heparin-produced cerebral hemorrhage. Targeting tPA and/or MMP 9 may provide a new approach to prevent cerebral hemorrhage associated with antithrombotic therapy in human stroke.
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