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 Blood, 8 October 2009, Vol. 114, No. 15, pp. 3352-3358.
Prepublished online as a Blood First Edition Paper on July 16, 2009; DOI 10.1182/blood-2009-02-203919.

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VASCULAR BIOLOGY

Tissue-type plasminogen activator (t-PA) induces stromelysin-1 (MMP-3) in endothelial cells through activation of lipoprotein receptor–related protein

Yasuhiro Suzuki1, Nobuo Nagai2, Kasumi Yamakawa3, Junichi Kawakami3, H. Roger Lijnen4, and Kazuo Umemura1

1 Department of Pharmacology, Hamamatsu University School of Medicine, Hamamatsu, Japan; 2 Department of Physiology, Kinki University School of Medicine, Osaka, Japan; 3 Department of Hospital Pharmacy, Hamamatsu University School of Medicine, Hamamatsu, Japan; and 4 Center for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium

Tissue-type plasminogen activator (t-PA) is approved for treatment of ischemic stroke patients, but it increases the risk of intracranial bleeding (ICB). Previously, we have shown in a mouse stroke model that stromelysin-1 (matrix metalloproteinase-3 [MMP-3]) induced in endothelial cells was critical for ICB induced by t-PA. In the present study, using bEnd.3 cells, a mouse brain–derived endothelial cell line, we showed that MMP-3 was induced by both ischemic stress and t-PA treatment. This induction by t-PA was prevented by inhibition either of low-density lipoprotein receptor–related protein (LRP) or of nuclear factor-{kappa}B activation. LRP was up-regulated by ischemic stress, both in bEnd.3 cells in vitro and in endothelial cells at the ischemic damage area in the mouse stroke model. Furthermore, inhibition of LRP suppressed both MMP-3 induction in endothelial cells and the increase in ICB by t-PA treatment after stroke. These findings indicate that t-PA deteriorates ICB via MMP-3 induction in endothelial cells, which is regulated through the LRP/nuclear factor-{kappa}B pathway.


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