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-B activation. LRP was upregulated by ischemic stress, both in bEnd. IntroductionTissue-type plasminogen activator (t-PA) is a thrombolytic agent that degrades fibrin clots through activation of plasminogen to plasmin. 1 Although t-PA given within 3 hours from onset of ischemic stroke improves the clinical outcome in patients, it induces a 10-fold increase of symptomatic intracranial bleeding (ICB). 2 Furthermore, delayed t-PA treatment beyond 3 hours is associated with an increased risk of hemorrhagic transformation and with enhanced brain injury. 3 The increase of ICB by delayed treatment with t-PA was also observed in a mouse stroke model. 4 Matrix metalloproteinases (MMPs), a family of zinc endopeptidases, contribute to tissue remodeling through degradation of extracellular matrix proteins. For ICB associated with ischemic stroke, MMPs have a key role in the degradation of the barrier of blood vessels. 5,6 Previously, we have shown that the increase in ICB caused by t-PA treatment was impaired in mice with gene deficiency of MMP-3 (stromelysin-1) and that a broad-spectrum MMP inhibitor suppressed ICB in wild-type but not in MMP-3-deficient mice. 7 MMP-3 can be activated by plasmin 8 and has a broad-spectrum substrate specificity. 9 Furthermore, t-PA treatment induced MMP-3 selectively in endothelial cells at the ischemic damaged area in a mouse stroke model, 7 suggesting that MMP-3 may be involved in degradation of the barrier of blood vessels and contribute to ICB. However, the mechanism underlying MMP-3 induction by t-PA remained unknown and is the subject of the present study.Low-density lipoprotein receptor-related protein (LRP), a member of the lipoprotein receptor family, is a scavenger receptor that binds a variety of biologic ligands and is thought to be primarily involved in lipoprotein metabolism 10 and in clearance of proteaseinhibitor complexes in the adult brain. 11 Recent reports have shown that t-PA induces MMP-9 in brain endothelial cells 12 and increases the blood-brain barrier permeability via LPR activation, 13 suggesting a role for LRP as a t-PA receptor. It has also been reported that LRP activation by t-PA stimulates the nuclear factor kappa-B (NF-B) pathway. 14 In this study, we have evaluated whether the LRP/NF-B pathway plays a role in MMP-3 induction by t-PA treatment. Therefore, we used bEnd.3 cells, a transformed endothelial cell line derived from mouse brain, as w...

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Tetrakis(triphenylphosphine)palladium(0) catalyzes the highly regioselectiVe addition of phenyl thiocyanate (PhSCN) to terminal alkynes, which attains the simultaneous introduction of thio and cyano groups to the internal and terminal positions of alkynes, respectiVely. This reaction may proceed Via the oxidatiVe addition of PhSCN to Pd(PPh 3 ) 4 , which forms Pd-(SPh)(CN)(PPh 3 ) 2 as the key intermediate.

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