title: Tissue-type plasminogen activator and the low-density lipoprotein receptor-related protein mediate cerebral ischemia-induced nuclear factor-kappaB pathway activation.
abstract: Tissue-type plasminogen activator (tPA) is a serine proteinase found in the intravascular space and the central nervous system. The low-density lipoprotein receptor-related protein (LRP) is a member of the low-density lipoprotein receptor gene family found in neurons and astrocytes. Cerebral ischemia induces activation of the nuclear factor (NF)-kappaB pathway. The present study investigated the role that the interaction between tPA and LRP plays on middle cerebral artery occlusion (MCAO)-induced NF-kappaB-mediated inflammatory response. We found that MCAO increased LRP expression primarily in astrocytes and that this effect was significantly decreased in the absence of tPA. The onset of the ischemic insult induced activation of the NF-kappaB pathway in wild-type and plasminogen (Plg(-/-))-deficient mice, and this effect was attenuated after inhibition of LRP or genetic deficiency of tPA. Moreover, administration of tPA to tPA(-/-) mice resulted in activation of the NF-kappaB pathway comparable with that observed in wild-type and Plg(-/-) mice. We also report that inhibition of either tPA activity or LRP or genetic deficiency of tPA resulted in a significant decrease in MCAO-induced nitric oxide production and inducible nitric-oxide synthase expression. In conclusion, our results demonstrate that after MCAO the interaction between tPA and LRP results in NF-kappaB activation in astrocytes and induction of inducible nitric-oxide synthase expression in the ischemic tissue, suggesting a cytokine-like plasminogen-independent role for tPA during cerebral ischemia.
authors: Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Whitehead Biomedical Research Bldg., 615 Michael St., Suite 505J, Atlanta, GA 30322, USA.
authors: Xiaohui
authors: X
authors: Zhang
authors: Rohini
authors: R
authors: Polavarapu
authors: Hua
authors: H
authors: She
authors: Zixu
authors: Z
authors: Mao
authors: Manuel
authors: M
authors: Yepes
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D002545:Brain Ischemia / Q000209:etiology / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D020244:Infarction, Middle Cerebral Artery / Q000150:complications*; D026502:LDL-Receptor Related Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010958:Plasminogen / Q000235:genetics; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000378:metabolism*
chemical_list: D026502:LDL-Receptor Related Proteins; D016328:NF-kappa B; D009569:Nitric Oxide; D010958:Plasminogen; D052247:Nitric Oxide Synthase Type II; D010959:Tissue Plasminogen Activator
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