Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The low-density lipoprotein receptor-related protein (LRP) is a member of the LDL receptor gene family that binds several ligands, including tissue-type plasminogen activator (tPA). tPA is found in blood, where its primary function is as a thrombolytic enzyme, and in the central nervous system where it mediates events associated with cell death. Cerebral ischemia induces changes in the neurovascular unit (NVU) that result in brain edema. We investigated whether the interaction between tPA and LRP plays a role in the regulation of the permeability of the NVU during cerebral ischemia. We found that the ischemic insult induces shedding of LRP's ectodomain from perivascular astrocytes into the basement membrane. This event associates with the detachment of astrocytic end-feet processes and the formation of areas of perivascular edema. The shedding of LRP's ectodomain is significantly decreased in tPA deficient (tPA(-/-)) mice, is increased by incubation with tPA, and is inhibited by the receptor-associated protein (RAP). Furthermore, treatment with either RAP or anti-LRP IgG results in a faster recovery of motor activity and protection of the integrity of the NVU following middle cerebral artery occlusion (MCAO). Together, these results implicate tPA/LRP interactions as key regulators of the integrity of the NVU.
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PMID:Tissue-type plasminogen activator-mediated shedding of astrocytic low-density lipoprotein receptor-related protein increases the permeability of the neurovascular unit. 1717 Jan 23

Lanoteplase is a recombinant mutant of tissue-type plasminogen activator (t-PA) that was developed with an aim to overcome the drawback of rapid systemic elimination of t-PA. In this study, we examined the disposition profile of lanoteplase in vivo and the kinetics of receptor-mediated endocytosis (RME) of this recombinant t-PA in vitro to kinetically characterize the mechanism(s) underlying its tissue distribution and elimination. Integration plot analysis of the initial-phase tissue distribution in rats revealed a much lower uptake clearance (CL(uptake)) of lanoteplase in the liver than that of t-PA. Rate constants for cell surface binding, internalization, and degradation of lanoteplase were also lower than those for t-PA in primary cultured rat hepatocytes. These results suggest that the improved stability of lanoteplase in vivo could be accounted for by the delay in the RME of this recombinant protein. The CL(uptake) in the liver decreased with coadministration of lactoferrin, a ligand for the low-density lipoprotein receptor-related protein (LRP) and the asialoglycoprotein (ASGP) receptors in normal mice, and in lrpap1((-/-)) mice, which have a hereditary deficiency of LRP; In contrast, CL(uptake) was not affected by mannose, whereas that of t-PA decreased with both ligands and in the lrpap1((-/-)) mice. Thus, the hepatic disposition of lanoteplase seems to be mediated by common specific receptors for t-PA, including LRP and the ASGP receptors, whereas the mannose receptor seems to be only minimally involved in the disposition of lanoteplase.
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PMID:Characterization of the hepatic disposition of lanoteplase, a rationally designed variant of tissue plasminogen activator in rodents. 1717 68

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.
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PMID:Tissue-type plasminogen activator and the low-density lipoprotein receptor-related protein mediate cerebral ischemia-induced nuclear factor-kappaB pathway activation. 1771 50

A suggestive locus on chromosome 8 could be shown to be associated with familial high factor VIII (FVIII) levels in venous thromboembolism. The ADAMDEC 1 gene is a candidate expressing an ectodomain sheddase. However, the ectodomain of the clearance receptor for FVIII, the low-density lipoprotein receptor-related protein (LRP), is subject to proteolysis by metalloproteases like ADAMDEC1. Other LRP-interacting proteins are lipoprotein lipase (LPL) and t-PA. For an association study, 165 thrombotic patients with high FVIII levels (from the MAISTHRO, i.e. Main-Isar-thrombosis register) were included. All patients with known causes for high FVIII levels had been previously excluded. The patients were compared with 214 healthy blood donors. Polymorphisms with usually a minor allele frequency >5%, i.e. 24 SNPs and two insertion/deletion polymorphisms of LPL gene, eight SNPs of the t-PA gene, and five SNPs of the ADAMDEC1 gene, were analyzed. Haplotype differences were calculated using PHASE. A new polymorphism in intron 7 of the t-PA gene with a minor allele frequency of 2.2% was identified. Analysis of each SNP by the Cochrane-Armitage trend test did not show any significant association between genotype and disease status. Interestingly, the ADAMDEC1 haplotype (rs12674766, rs10087305, rs2291577, rs2291578, rs3765124) differed between cases and controls (p = 0.04). In particular, the TGTGG haplotype showed a difference. In conclusion, the ADAMDEC 1 haplotype may indicate an underlying mechanism for high FVIII levels. The only moderate linkage disequilibrium may be due to a possible causal polymorphism in distant introns or the promoter region against a polygenic background.
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PMID:Association of ADAMDEC1 haplotype with high factor VIII levels in venous thromboembolism. 1844 20

Tissue-type plasminogen activator (tPA) is found in the intravascular space and in the central nervous system. The low-density lipoprotein receptor-related protein (LRP) is expressed in neurons and in perivascular astrocytes. During cerebral ischemia, tPA induces the shedding of LRP's extracellular domain from perivascular astrocytes, and this is followed by the development of cerebral edema. Protein kinase B (Akt) is a serine/threonine kinase that plays a critical role not only in cell survival but also in the regulation of the permeability of the blood-brain barrier. We found that, in the early phases of the ischemic insult, the interaction between tPA and LRP induces Akt phosphorylation (pAkt) in perivascular astrocytes and inhibits pAkt in neurons. Coimmunoprecipitation studies indicate that pAkt and LRP's intracellular domain interact in perivascular astrocytes and that this interaction is dependent on the presence of tPA and results in the development of edema. Together, these results indicate that, in the early stages of cerebral ischemia, the interaction between tPA and LRP in perivascular astrocytes induces the activation of a cell signaling event mediated by pAkt that leads to increase in the permeability of the blood-brain barrier.
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PMID:Tissue-type plasminogen activator and the low-density lipoprotein receptor-related protein induce Akt phosphorylation in the ischemic brain. 1862 88

Glutamate is the main excitatory neurotransmitter of the CNS. Tissue-type plasminogen activator (tPA) is recognized as a modulator of glutamatergic neurotransmission. This attribute is exemplified by its ability to potentiate calcium signaling following activation of the glutamate-binding NMDA receptor (NMDAR). It has been hypothesized that tPA can directly cleave the NR1 subunit of the NMDAR and thereby potentiate NMDA-induced calcium influx. In contrast, here we show that this increase in NMDAR signaling requires tPA to be proteolytically active, but does not involve cleavage of the NR1 subunit or plasminogen. Rather, we demonstrate that enhancement of NMDAR function by tPA is mediated by a member of the low-density lipoprotein receptor (LDLR) family. Hence, this study proposes a novel functional relationship between tPA, the NMDAR, a LDLR and an unknown substrate which we suspect to be a serpin. Interestingly, whilst tPA alone failed to cleave NR1, cell-surface NMDARs did serve as an efficient and discrete proteolytic target for plasmin. Hence, plasmin and tPA can affect the NMDAR via distinct avenues. Altogether, we find that plasmin directly proteolyses the NMDAR whilst tPA functions as an indirect modulator of NMDA-induced events via LDLR engagement.
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PMID:Tissue-type plasminogen activator requires a co-receptor to enhance NMDA receptor function. 1879 5

Microglia are the immune cells of the central nervous system (CNS) that become activated in response to pathological situations such as cerebral ischemia. Tissue-type plasminogen activator (tPA) is a serine proteinase that is found in the intravascular space and the CNS. The low-density lipoprotein receptor-related protein 1 (LRP1) is a member of the low-density lipoprotein receptor gene family found in neurons, astrocytes, and microglia. The present study investigated whether the interaction between tPA and microglial LRP1 plays a role in cerebral ischemia-induced microglial activation. We found that middle cerebral artery occlusion (MCAO) induces microglial activation in both wild-type and plasminogen-deficient (Plg(-/-)) mice. In contrast, MCAO-induced microglial activation is significantly decreased in tPA-deficient (tPA(-/-)) mice and in mice that lack LRP1 in microglial cells (macLRP(-)). We observed a significant increase in microglial activation when tPA(-/-) mice received treatment with murine tPA after MCAO. In contrast, treatment of macLRP(-) mice with tPA did not have an effect on the extent of microglial activation. Finally, both the volume of the ischemic lesion as well as inducible nitric oxide synthase production were significantly decreased in macLRP(-) mice and macLRP(-) microglia. In summary, our results indicate that the interaction between tPA and LRP1 induces microglial activation with the generation of an inflammatory response in the ischemic brain, suggesting a cytokine-like role for tPA in the CNS.
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PMID:The low-density lipoprotein receptor-related protein 1 mediates tissue-type plasminogen activator-induced microglial activation in the ischemic brain. 1914 18

Chronic kidney disease (CKD) is estimated to affect one in eight adults. Their kidney function progressively deteriorates as inflammatory and fibrotic processes damage nephrons. New therapies to prevent renal functional decline must build on basic research studies that identify critical cellular and molecular mediators. Plasminogen activator inhibitor-1 (PAI-1), a potent fibrosis-promoting glycoprotein, is one promising candidate. Absent from normal kidneys, PAI-1 is frequently expressed in injured kidneys. Studies in genetically engineered mice have demonstrated its potency as a pro-fibrotic molecule. Somewhat surprising, its ability to inhibit serine protease activity does not appear to be its primary pro-fibrotic effect in CKD. Both tissue-type plasminogen activator and plasminogen deficiency significantly reduced renal fibrosis severity after ureteral obstruction, while genetic urokinase (uPA) deficiency had no effect. PAI-1 expression is associated with enhanced recruitment of key cellular effectors of renal fibrosis - interstitial macrophages and myofibroblasts. The ability of PAI-1 to promote cell migration involves interactions with the low-density lipoprotein receptor-associate protein-1 and also complex interactions with uPA bound to its receptor (uPAR) and several leukocyte and matrix integrins that associate with uPAR as co-receptors. uPAR is expressed by several cell types in damaged kidneys, and studies in uPAR-deficient mice have shown that its serves a protective role. uPAR mediates additional anti-fibrotic effects - it interacts with specific co-receptors to degrade PAI-1 and extracellular collagens, and soluble uPAR has leukocyte chemoattractant properties. Molecular pathways activated by serine proteases and their inhibitor, PAI-1, are promising targets for future anti-fibrotic therapeutic agents.
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PMID:Serine proteases, inhibitors and receptors in renal fibrosis. 1935 Jan 8

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.
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PMID:Tissue-type plasminogen activator (t-PA) induces stromelysin-1 (MMP-3) in endothelial cells through activation of lipoprotein receptor-related protein. 1981 79

Studies in animal models of cerebral ischemia indicate that besides its thrombolytic effect, treatment with tissue-type plasminogen activator (tPA) also induces an increase in matrix metalloproteinase-9 (MMP-9) activity in the ischemic tissue associated with the development of cerebral edema. Earlier, we had shown that the low-density lipoprotein receptor-related protein 1 (LRP1) is a substrate for tPA in the brain. In this study, we investigated the effect of the interaction between tPA and microglial LRP1 on MMP-9 activity after middle cerebral artery occlusion (MCAO). We found that exposure to oxygen-glucose deprivation (OGD) conditions increases MMP-9 activity in wild-type (Wt) and plasminogen-deficient (Plg(-/-)) microglia, but not in tPA (tPA(-/-)) or LRP1-deficient (macLRP-) cells. Treatment with tPA increases MMP-9 expression in tPA(-/-) but not in macLRP- microglia. Middle cerebral artery occlusion increases MMP-9 expression and activity in Wt but not in tPA(-/-) or macLRP- mice, and treatment with tPA increases MMP-9 activity in tPA(-/-) mice but not in macLRP- animals. Finally, MCAO-induced ischemic edema and degradation of the interendothelial right junction protein claudin-5 were significantly attenuated in tPA(-/-) and macLRP- mice. The results of our study indicate that the interaction between tPA and microglial LRP1 increases MMP-9 expression and activity resulting in the degradation of claudin-5 and development of cerebral edema.
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PMID:Microglial low-density lipoprotein receptor-related protein 1 mediates the effect of tissue-type plasminogen activator on matrix metalloproteinase-9 activity in the ischemic brain. 1967 75


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