期刊
BLOOD
卷 114, 期 15, 页码 3352-3358出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2009-02-203919
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资金
- Mitsubishi Pharma Research Foundation
- Ministry of Education Culture of Japan [20790204]
- Excellentie Financiering KU Leuven [EF/05/013]
- Grants-in-Aid for Scientific Research [20790204] Funding Source: KAKEN
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 upregulated 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. (Blood. 2009; 114: 3352-3358)
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