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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. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-03-0835v1 103/7/2610    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Zhao, B.-Q. Articles by Umemura, K. Search for Related Content PubMed PubMed Citation Articles by Zhao, B.-Q. Articles by Umemura, K. Related Collections Hemostasis, Thrombosis, and Vascular Biology Gene Expression Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Essential role of endogenous tissue plasminogen activator through 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 From the Departments of Pharmacology, Physiology, and Anatomy and Neuroscience, Hamamatsu University School of Medicine, Japan; and the Center for Molecular and Vascular Biology, Leuven University, Belgium. Cerebral hemorrhage associated with antithrombotic and thrombolytic therapy in acute stroke continues to present a major clinical problem. Rupture of the cerebral microvasculature involves the degradation and remodeling of extracellular matrix. Here we demonstrated that the 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 knockout (KO) mice. Heparin administration increased tPA activity and its mRNA expression at 6 and 12 hours after MCAO in the ischemic hemispheres of WT mice. The expression of tPA was enhanced in microglial cells in the ischemic border zone. We also observed an exacerbation of matrix metalloproteinase (MMP) 9 expression at the mRNA level and its conversion to an active form after 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, through the enhancement of MMP 9 expression and proteolytic activation, plays an essential role in the pathogenesis of heparin-produced cerebral hemorrhage. Targeting tPA, MMP 9, or both may provide a new approach for preventing cerebral hemorrhage associated with antithrombotic therapy for stroke in humans. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: K. Liu, S. Mori, H. K. Takahashi, Y. Tomono, H. Wake, T. Kanke, Y. Sato, N. Hiraga, N. Adachi, T. Yoshino, et al. Anti-high mobility group box 1 monoclonal antibody ameliorates brain infarction induced by transient ischemia in rats FASEB J, December 1, 2007; 21(14): 3904 - 3916. [Abstract] [Full Text] [PDF] M. Hurtado, J. J. Lozano, E. Castellanos, L. A Lopez-Fernandez, K. Harshman, C. Martinez-A, A. R Ortiz, T. M Thomson, and R. Paciucci Activation of the epidermal growth factor signalling pathway by tissue plasminogen activator in pancreas cancer cells Gut, September 1, 2007; 56(9): 1266 - 1274. [Abstract] [Full Text] [PDF] M. Ning, K. L. Furie, W. J. Koroshetz, H. Lee, M. Barron, M. Lederer, X. Wang, M. Zhu, A. G. Sorensen, E. H. Lo, et al. Association between tPA therapy and raised early matrix metalloproteinase-9 in acute stroke Neurology, May 23, 2006; 66(10): 1550 - 1555. [Abstract] [Full Text] [PDF] Z. Gu, J. Cui, S. Brown, R. Fridman, S. Mobashery, A. Y. Strongin, and S. A. Lipton A Highly Specific Inhibitor of Matrix Metalloproteinase-9 Rescues Laminin from Proteolysis and Neurons from Apoptosis in Transient Focal Cerebral Ischemia J. Neurosci., July 6, 2005; 25(27): 6401 - 6408. [Abstract] [Full Text] [PDF]

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