The primary plasminogen-activator inhibitors in endothelial cells, platelets, serum, and plasma are immunologically related.

Erickson, Laurence A.; Hekman, Carla M.; Loskutoff, David J.

doi:10.1073/pnas.82.24.8710

Cited by 142 publications

(80 citation statements)

References 40 publications

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“…PAI-1 is a known physiological inhibitor for both tPA and uPA and regulates PA proteolytic activity (Hekman and Loskutoff, 1988). It is expressed by various cell types including endothelial cells, neutrophils, macrophages, and platelets, and is present in plasma and bound to the extracellular matrix (Erickson et al, 1985;Podor and Loskutoff, 1992;Loskutoff et al, 1994;Haj et al, 1995). Thus, induction of PAI-1 activity might also occur after nerve injury, concurrent with the increases seen in PA activity.…”

Section: Pa Inhibitor Activity At the Crush Sitementioning

confidence: 99%

Induction of the Plasminogen Activator System Accompanies Peripheral Nerve Regeneration after Sciatic Nerve Crush

Siconolfi

Seeds

2001

J. Neurosci.

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Peripheral nerve regeneration is dependent on the ability of regenerating neurites to migrate through cellular debris and altered extracellular matrix at the injury site, grow along the residual distal nerve sheath conduit, and reinnervate synaptic targets. In cell culture, growth cones of regenerating axons secrete proteases, specifically plasminogen activators (PAs), which are believed to facilitate growth cone movement by digesting extracellular matrices and cell adhesions. In this study, the PA system was shown to be specifically activated in sensory neurons after sciatic nerve crush in adult mice. The number of sensory neurons expressing urokinase PA receptor (uPAR) mRNA levels increased above sham levels by 8 hr after crush, whereas the number of sensory neurons expressing uPA and tissue PA (tPA) mRNAs was significantly increased by 3 d after crush. PA mRNA levels were also increased at the crush site, with uPA mRNA elevated by 8 hr after crush and tPA and uPAR mRNA levels markedly increased by 7 d. PA-dependent enzymatic activity was significantly increased from 1 to 7 d after crush in nerves that had been crushed compared with uncrushed nerves. Immunohistochemistry showed that tPA was localized within regenerating axons of the sciatic nerve. There were no significant changes in plasminogen activator inhibitor 1 activity between crush and sham after the injury. These results clearly demonstrated that after injury the PA system was rapidly induced in sensory neurons, where it may play an important role in nerve regeneration in vivo.

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Section: Pa Inhibitor Activity At the Crush Sitementioning

confidence: 99%

Induction of the Plasminogen Activator System Accompanies Peripheral Nerve Regeneration after Sciatic Nerve Crush

Siconolfi

Seeds

2001

J. Neurosci.

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“…3 PAI-1 is a 50-kd glycoprotein from the serpin superfamily. 4 It can be produced by platelets, vascular endothelial cells, 5 vascular smooth muscle cells, 6 and several nonvascular cell types, 7,8 including hepatocytes. 9 PAI-1 has also been identified as a component of the extracellular matrix.…”

Section: Introductionmentioning

confidence: 99%

The upstream stimulatory factor-2a inhibits plasminogen activator inhibitor-1 gene expression by binding to a promoter element adjacent to the hypoxia-inducible factor-1 binding site

Samoylenko¹,

Roth²,

Jungermann³

et al. 2001

Blood

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Plasminogen activator inhibitor-1 (PAI-1) expression is induced by hypoxia (8% O 2 ) via the PAI-1 promoter region ؊175/؊159 containing a hypoxia response element (HRE-2) binding the hypoxia-inducible factor-1 (HIF-1) and an adjacent response element (HRE-1) binding a so far unknown factor. The aim of the present study was to identify this factor and to investigate its role in the regulation of PAI-1 expression. It was found by supershift assays that the upstream stimulatory factor-2a (USF-2a) bound mainly to the HRE-1 of the PAI-1 promoter and to a lesser extent to HRE-2. Overexpression IntroductionThe tissue-type and the urokinase-type plasminogen activators (tPA and uPA) are serine proteases converting the inactive zymogen plasminogen to the active endopeptidase plasmin. 1 The tPA and uPA activity is regulated, in part, by plasminogen activator inhibitors (PAIs). 2 Among 2 identified inhibitors, PAI-1 and PAI-2, PAI-1 is the primary physiologic inhibitor of both tPA and uPA. 3 PAI-1 is a 50-kd glycoprotein from the serpin superfamily. 4 It can be produced by platelets, vascular endothelial cells, 5 vascular smooth muscle cells, 6 and several nonvascular cell types, 7,8 including hepatocytes. 9 PAI-1 has also been identified as a component of the extracellular matrix. 10 The plasminogen activator inhibitors are involved in many functions, both under normal and pathological conditions, including fibrinolysis, extracellular matrix turnover, and fibrosis. 11 PAI-1 also participates in wound healing and cancer metastasis. 12,13 Certain pathophysiologic processes in which PAI-1 levels increase (eg, prethrombotic events, hemorrhage, and thrombus formation) are associated with hypoxia. PAI-1 gene expression was induced by mild hypoxia (8% O 2 ) via an O 2 -responsive promoter sequence (Ϫ175/Ϫ158) containing hypoxia response element-1 (HRE-1, Ϫ175/Ϫ168) and hypoxia response element-2 (HRE-2, Ϫ165/Ϫ158) in primary cultured rat hepatocytes. 14 HRE-2 was shown to bind the hypoxia-inducible factor-1 (HIF-1) and thus to be most critical for the increase in PAI-1 gene expression under hypoxia. The HRE-1 sequence was shown to bind a factor other than HIF-1.The HRE-1 and also HRE-2 include a CACGTG-like sequence that can be recognized by transcription factors containing basic helix-loop-helix (bHLH) domains. Besides HIF-1 consisting of the bHLH-PAS (Per-ARNT-Sim) domain proteins HIF-1␣ and HIF-1␤ (ARNT, or arylhdrocarbon receptor nuclear translocator), 15 the bHLH leucine zipper (bHLH-zip) proteins, upstream stimulatory factors (USF), 16 or the Myc/Max 16,17 transcription factors also can bind to the CACGTG sequence. USF was initially identified in HeLa cells as a protein binding the CACGTG sequence located immediately upstream of the TATA sequence of the adenovirus major late promoter, 16 thereby activating transcription. 18 Two different ubiquituously expressed forms of USF (USF-1 and USF-2) with different molecular weights have been identified; however, their relative abundance varies in different cell types. 19,20 The US...

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“…The high-molecular-mass t-PA in plasma is now known to be an equimolar complex of t-PA with a plasminogen activator inhibitor (PAI) [3, 41. Inhibitors active against both t-PA and u-PA have been discovered in bovine [6] and human [7 -91 endothelial cells, in platelets [lo, 111 and in plasma [3, 12 -141. Immunological cross-reactivity between the bovine endothelial and human platelet inhibitor has been established [15] and this type of PA1 is now designated PAI-1 [16].…”

mentioning

confidence: 99%

“…Inhibitors active against both t-PA and u-PA have been discovered in bovine [6] and human [7 -91 endothelial cells, in platelets [lo, 111 and in plasma [3, 12 -141. Immunological cross-reactivity between the bovine endothelial and human platelet inhibitor has been established [15] and this type of PA1 is now designated PAI-1 [16].The bovine endothelial cell PA1 is in an inactive or latent form that is converted to an active form in the presence of denaturants such as SDS and guanidinium hydrochloride [17]. This inhibitor has been purified using SDS/polyacrylamide gel electrophoresis (SDS-PAGE) as the final preparative step; thus the purified product was active [18].…”

mentioning

confidence: 99%

Plasminogen activator inhibitor from human endothelial cells. Purification and partial characterization

et al. 1987

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An inhibitor of plasminogen activator was purified to apparent homogeneity from human umbilical vein endothelial cell conditioned medium. The purification was achieved by a speedy and simple two-step procedure, without the use of denaturants. The purified protein was a single-chain glycoprotein with apparent molecular mass of 48 kDa.The purified inhibitor had a specific activity of 8500 U/mg protein and the activity could be stimulated about fourteenfold by treatment with denaturants.An antiserum to the purified inhibitor was raised in rabbits. It recognised plasminogen activator inhibitor from platelets and plasma as well as from cultured endothelial cells. The immunoglobulin fraction of the antiserum neutralised the functional activity of the inhibitor from all these sources.The activity of the fibrinolytic system depends on the cleavage of the zymogen plasminogen to form plasmin by plasminogen activators. Two major immunologically distinct types of plasminogen activator, tissue-type (tPA) and urokinase (u-PA) have been identified (reviewed in [l]). t-PA is present in normal resting plasma at a molecular mass of about 110 kDa [2 -41, in contrast to the 65-kDa form isolated from tissues [5]. The high-molecular-mass t-PA in plasma is now known to be an equimolar complex of t-PA with a plasminogen activator inhibitor (PAI) [3, 41. Inhibitors active against both t-PA and u-PA have been discovered in bovine [6] and human [7 -91 endothelial cells, in platelets [lo, 111 and in plasma [3, 12 -141. Immunological cross-reactivity between the bovine endothelial and human platelet inhibitor has been established [15] and this type of PA1 is now designated PAI-1 [16].The bovine endothelial cell PA1 is in an inactive or latent form that is converted to an active form in the presence of denaturants such as SDS and guanidinium hydrochloride [17]. This inhibitor has been purified using SDS/polyacrylamide gel electrophoresis (SDS-PAGE) as the final preparative step; thus the purified product was active [18].In the study reported here, we aimed to purify PA1 from human endothelial cells in the absence of denaturants. T h s Correspondence to

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The primary plasminogen-activator inhibitors in endothelial cells, platelets, serum, and plasma are immunologically related.

Cited by 142 publications

References 40 publications

Induction of the Plasminogen Activator System Accompanies Peripheral Nerve Regeneration after Sciatic Nerve Crush

Induction of the Plasminogen Activator System Accompanies Peripheral Nerve Regeneration after Sciatic Nerve Crush

The upstream stimulatory factor-2a inhibits plasminogen activator inhibitor-1 gene expression by binding to a promoter element adjacent to the hypoxia-inducible factor-1 binding site

Plasminogen activator inhibitor from human endothelial cells. Purification and partial characterization

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