Disease relevance of Plat

• Progeny studies using NZW x (NZW x BXSB) F1 male backcross mice showed that the BXSB Plat allele was significantly associated with high levels of both platelet-binding antibodies and thrombocytopenia [1].
• Thus, the BXSB-type Plat may be one susceptibility allele for the multigenic antiphospholipid syndrome seen in (NZW x BXSB) F1 mice [1].
• We also show that injection of tPA into the cerebrospinal fluid in the absence of ischemia results in a rapid dose-dependent increase in vascular permeability [2].
• Tissue-type plasminogen activator (tPA) is one of the major components in the matrix proteolytic network whose role in the pathogenesis of renal interstitial fibrosis remains largely unknown [3].
• Mice lacking tPA developed less morphological injury and displayed a reduced deposition of interstitial collagen III and fibronectin as well as total tissue collagen in the kidneys after sustained ureteral obstruction, when compared with their wild-type counterparts [3].

Psychiatry related information on Plat

• This treatment regime had no effect on locomotor activity in either genotype. tPA-/- mice showed no spatial learning deficits, but were more sensitive to dizocilpine during acquisition (though not expression) of a DRL task [4].
• Targeted disruption of tPA release or its upstream regulation by glutamic acid decarboxylase (GAD65) prevented MD-induced spine loss that was pharmacologically rescued concomitant with critical period plasticity [5].
• The learning disability of tPA -/- was overcome by more intense training [6].
• Consistently, in Alzheimer's disease (AD) patients' brains, high levels of tPA colocalize with amyloid-rich areas, activated Erk1/2 and phosphorylated tau [7].
• These results support our hypothesis that tPA plays a role in long-lasting neuronal changes related to drug dependence [8].

High impact information on Plat

• Excess excitatory amino acids can provoke neuronal death in the hippocampus, and the extracellular proteases tissue plasminogen activator (tPA) and plasmin (ogen) have been implicated in this death [9].
• These results indicate that disruption of neuron-ECM interaction via tPA/plasmin catalyzed degradation of laminin sensitizes hippocampal neurons to cell death [9].
• Therefore, the stage-specific regulation of poly(A) tail length accounts for the regulated synthesis of tPA in oocytes, and reversible deadenylation provides a mechanism for the translational control of dormant mRNAs [10].
• Activated protein C (APC), a serine protease with anticoagulant, anti-inflammatory and antiapoptotic activities, which is neuroprotective during transient ischemia and promotes activation of antiapoptotic mechanisms in brain cells by acting directly on endothelium and neurons, blocked tPA vascular and neuronal toxicities in vitro and in vivo [11].
• In human cerebral microvascular endothelial cells, MMP-9 was upregulated when recombinant tPA was added [12].

Chemical compound and disease context of Plat

• Morphometric analysis of injured arterial segments revealed severe luminal stenosis (62+/-28%) in uPA(-/-) mice compared with their tPA(-/-) (16+/-12%) and WT (6.3+/-3.6%, P<0.001) counterparts [13].
• These findings suggest that endogenous tPA, through the enhancement of MMP 9 expression and proteolytic activation, plays an essential role in the pathogenesis of heparin-produced cerebral hemorrhage [14].
• In line, tPA(-/-) mice demonstrated a reduced thioglycolate-induced neutrophil influx into the peritoneal cavity and i.p. injection of WT mice with a replication-defective adenoviral vector expressing tPA caused an enhanced cell migration to the peritoneal cavity during E. coli peritonitis [15].
• The number of TUNEL-positive cells in ganglion cell layer (GCL) and inner nuclear layer (INL) in tPA-deficient mice after low-, but not high-dose NMDA was significantly less compared to wild type [16].
• We investigated cocaine-induced locomotor activity, the development of sensitisation to cocaine and cocaine self-administration in mice lacking the gene encoding tPA [17].

Biological context of Plat

• In the present studies, sequence analyses for structural and promoter regions of Plat revealed a single nucleotide polymorphism encoding a catalytic domain of t-PA, with an amino acid substitution of anionic Glu366 in NZW for a cationic Lys in BXSB [1].
• Our earlier genetic studies showed that one susceptibility allele for thrombocytopenia and associated IgG platelet-binding autoantibodies in male (NZW x BXSB) F1 mice was linked to the BXSB-type polymorphic microsatellite D8Mit96, located in proximity to the gene Plat for tissue-type plasminogen activator (t-PA) [1].
• The gene for the mouse low affinity receptor for IgE (Fc epsilon RII, also known as CD23) was mapped on Chromosome (Chr) 8 proximal to Plat [18].
• Together these studies demonstrate that tPA is both necessary and sufficient to directly increase vascular permeability in the early stages of BBB opening, and suggest that this occurs through a receptor-mediated cell signaling event and not through generalized degradation of the vascular basement membrane [2].
• Plasminogen activation independent of uPA and tPA maintains wound healing in gene-deficient mice [19].

Anatomical context of Plat

• Deficiency of tPA selectively blocked tubular epithelial-to-myofibroblast transition (EMT), but did not affect myofibroblastic activation from interstitial fibroblasts [3].
• Consistent with this possibility, tPA-/- and plasminogen-/- mice are protected from stress-induced decrease in NMDA receptors and reduction in dendritic spines [20].
• Wild-type and tPA-/- mice completely repaired experimentally damaged skeletal muscle [21].
• Induction of expression of tPA and PAI-1 transcripts was detected in activated astrocytes in the white matter [22].
• Collectively, these results suggest that besides its classical proteolytic activity, tPA acts as a cytokine that binds to the cell membrane receptor LRP-1, induces its tyrosine phosphorylation, and triggers intracellular signal transduction, thereby inducing specific gene expression in renal interstitial fibroblasts [23].

Associations of Plat with chemical compounds

• Tissue plasminogen activator (tPA) is a serine protease involved in the degradation of blood clots through the activation of plasminogen to plasmin [24].
• These findings demonstrate that an additional plasminogen activator provides sufficient plasmin activity to sustain the healing process albeit at decreased speed in the absence of uPA, tPA and galardin-sensitive MMPs and suggest that pKal plays a role in plasmin generation [19].
• Strikingly, the stress-induced decrease in NMDA receptors coincides spatially with sites of plasminogen activation, thereby predicting a role for tissue plasminogen activator (tPA) in this form of stress-induced plasticity [20].
• Nitric oxide mediates neurodegeneration and breakdown of the blood-brain barrier in tPA-dependent excitotoxic injury in mice [25].
• We examine here the potentially interrelated roles of tPA, NO and peroxynitrite (ONOO-), which is the toxic metabolite of NO, in BBB breakdown and neurodegeneration following intrahippocampal injection of the glutamate analog kainite (KA) [25].

Physical interactions of Plat

• Furthermore, these two traits appeared to be regulated by a complementary effect of two BXSB alleles; one is linked to Plat and the other to the H-2 complex and the gene for plasminogen [1].

Enzymatic interactions of Plat

• In addition, B16F10 melanoma-associated t-PA catalyzes the plasminogen-dependent hydrolysis of laminin [26].

Co-localisations of Plat

• Fibrin autography of storage granules revealed a prominent lytic zone at Mr 66 kD comigrating with free t-PA [27].

Regulatory relationships of Plat

• This study investigated the mechanism by which tPA induces MMP-9 gene expression [23].
• Here, we report that BDNF stimulates the expression of tissue-type plasminogen activator (tPA) in primary cultures of cortical neurons in a time- and concentration-dependent manner [28].
• Our data highlight the complexities of PA function, and suggest that approaches either to target u-PA or to enhance local t-PA activity in joints may be of therapeutic benefit in rheumatoid arthritis [29].
• Analysis of plasminogen activator inhibitor-1 (PAI-1) expression showed that PAI-1 antigen is upregulated by 24 hr and could account for the tPA activity downregulation seen at this time point [30].
• In the embryonic spinal cord, PN-1 expression occurs in cells lining the neural canal that are different from the cells previously shown to express tPA [31].

Other interactions of Plat

• The results revealed that tPA played the most important role in local regulation of fibrin deposition in the heart, with lesser contributions by TM and uPA (least significant) [32].
• A marked decrease in matrix metalloproteinase-9 (MMP-9) induction was found in the obstructed kidneys of tPA(-/-) mice, which led to a dramatic preservation of the structural and functional integrity of tubular basement membrane (TBM) [3].
• Moreover, a synergistic relationship in fibrin formation existed in mice with concomitant modifications of tPA and TM, resulting in myocardial necrosis and depressed cardiac function [32].
• We further demonstrate that growth of primary fibroblasts in culture is dependent on a tPA-mediated cleavage of latent PDGF-CC, generating a growth stimulatory loop [24].
• We report a comparative study of animals with individual and combined deficits in uPAR and tPA and show that these proteins are complementary fibrinolytic factors in mice [33].

Analytical, diagnostic and therapeutic context of Plat

• Homologous recombination at the t-PA, u-PA and PAI-1 locus was verified by Southern blot analysis of genomic tail tip DNA, and confirmed by measurement of antigen levels in plasma or urine [34].
• Immunostaining and western blot analysis was performed to detect uPA and tPA proteins [35].
• RESULTS: In wild-type mice, tPA delivered immediately after ischemia significantly increased infarct volume 24 hours after reperfusion [36].
• Here we show that tPA upregulates MMP-9 in cell culture and in vivo [12].
• In experimental embolic stroke models, MMP inhibitors decreased cerebral hemorrhage and injury after treatment with tPA [12].

References