Tissue-type plasminogen activator (t-PA) induces stromelysin-1 (MMP-3) in endothelial cells through activation of lipoprotein receptor-related protein.
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-kappaB 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-kappaB pathway.
Suzuki
Yasuhiro
Y
Department of Pharmacology, Hamamatsu University School of Medicine, Hamamatsu, Japan, Japan.
Nagai
Nobuo
N
Yamakawa
Kasumi
K
Kawakami
Junichi
J
Lijnen
H Roger
HR
Umemura
Kazuo
K
D000818:Animals; D002545:Brain Ischemia / Q000201:enzymology* / Q000235:genetics; D002461:Cell Line, Transformed; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000201:enzymology*; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D020521:Stroke / Q000201:enzymology* / Q000235:genetics; D010959:Tissue Plasminogen Activator / Q000494:pharmacology*
D026502:LDL-Receptor Related Proteins; D016328:NF-kappa B; D010959:Tissue Plasminogen Activator; D019278:Matrix Metalloproteinase 3; C511769:Mmp3 protein, mouse