Disease relevance of SERPINE1

• Hyperglycemia increased expression from an 85-bp truncated plasminogen activator inhibitor-1 (PAI-1) promoter luciferase reporter containing two Sp1 sites in a similar fashion (3.8-fold) [1].
• Furthermore, the effect of short-term anoxia on PA and PAI could not be reversed by reoxygenation for 24 hours [2].
• Local accumulation of plasminogen activator inhibitor-1 (PAI-1) in response to thrombosis has been implicated not only in inhibition of fibrinolysis but also in the pathogenesis of vascular disease [3].
• Glucocorticoids decrease plasminogen activator (PA) activity in HTC rat hepatoma cells by inducing a specific inhibitor of PA activity (PAI) [4].
• Circadian variation in plasminogen activator inhibitor-1 (PAI-1) production likely contributes to increased risk of myocardial infarction and decreased efficacy of thrombolytic therapy during the morning [5].

High impact information on SERPINE1

• Angiotensin induction of PAI-1 expression in endothelial cells is mediated by the hexapeptide angiotensin IV [6].
• These results indicate that the hexapeptide Ang IV is the form of angiotensin that stimulates endothelial expression of PAI-1 [6].
• Although larger forms of angiotensin (i.e., Ang I, Ang II, and Ang III) are capable of inducing PAI-1 expression, this property is lost in the presence of converting enzyme or aminopeptidase inhibitors [6].
• Furthermore, both TGase inhibitors and a neutralizing antibody to TGase potentiated the effect of retinol in enhancing plasminogen activator (PA) levels in cultures of BAECs by suppressing the TGF-beta-mediated enhancement of PA inhibitor-1 (PAI-1) expression [7].
• However, the kinetics and amplitude of PAI-1 and u-PA mRNA induction by these agents are strikingly different [8].

Biological context of SERPINE1

• Preincubation of thrombin with hirudin, a specific inhibitor of thrombin, or with D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone, an inhibitor of the active site of thrombin, prevented the induction of PAI-1 synthesis [3].
• This effect was attributed to a moderate upregulation of urokinase-type PA expression as well as to a significant down-regulation of PA inhibitor-1 (PAI-1) expression [9].
• IL-1 induced increases in PAI-1 production in EC transfected with reporter genes alone [10].
• The resultant TGF-beta suppresses the excessive fibrinolytic activity by decreasing PA expression and stimulating expression of the PA inhibitor, PA inhibitor-1 (PAI-1), and inhibits cell proliferation [11].
• Both CLOCK:BMAL1 and CLOCK:BMAL2 heterodimers activate the PAI-1 promoter through requisite proximal (-565 to -560 bp) and distal (-680 to -675 bp) E-box enhancers [5].

Anatomical context of SERPINE1

• We also find that transforming growth factor-beta 1 (TGF-beta 1), which in vitro modulates a number of endothelial cell functions relevant to angiogenesis, also increases both PAI-1 and urokinase-type PA (u-PA) mRNA [8].
• The extracellular matrix (ECM) of cultured bovine aortic endothelial cells (BAEs) was analyzed by immunoblotting and reverse fibrin autography and shown to contain type 1 plasminogen activator inhibitor (PAI-1) [12].
• Thrombin, in the absence of serum, induced production of PAI-1 by bovine aortic smooth muscle cells in a dose-dependent manner [3].
• To determine whether thrombin, known to be released from thrombi, can induce expression of PAI-1 in vascular smooth muscle, bovine aortic smooth muscle cells were exposed to highly purified bovine thrombin [3].
• RESULTS: The data indicated that ASU stimulate the expression of TGFbeta1, TGFbeta2, and PAI-1 by articular chondrocytes [13].

Associations of SERPINE1 with chemical compounds

• Recent studies from this laboratory have demonstrated that angiotensin II (Ang II) stimulates the expression of plasminogen activator inhibitor 1 (PAI-1) in cultured endothelial cells [6].
• The PAI-1 could not be removed by incubating ECM in high salt (2 mol/L NaCl), sugars (1 mol/L galactose, 1 mol/L mannose), glycosaminoglycans (10 mmol/L heparin, 10 mmol/L dermatan sulfate), or epsilon-aminocaproic acid (0.1 mol/L) [12].
• (1) Infusion of thrombin in rabbits made deficient in vitamin K-dependent plasma proteins by warfarin treatment did not result in modification of PAI activity [14].
• However, PAI-1 could be extracted from ECM by treatment with either arginine (0.5 mol/L) or potassium thiocyanate (2 mol/L), or by incubation under acidic conditions (pH 2.5) [12].
• For example, less than 0.01 units/microliter of PAI activity was detected in untreated conditioned medium, but medium treated with sodium dodecyl sulfate (1.7 mM), guanidine HCl (4 M), urea (12 M) or KSCN (6 M) contained 0.9, 1.9, 0.8, and 0.5 units/microliter, respectively [15].

Physical interactions of SERPINE1

• Alanine substitutions at the distal P4' (Glu-350) and P5' (Glu-351) residues of PAI-1 reduced the rates of Michaelis complex formation (k(a)) and overall inhibition (k(app)) with tPA by 13.4- and 4.7-fold, respectively, whereas the rate of loop insertion or final acyl-enzyme formation (k(lim)) increased by 3.3-fold [16].

Regulatory relationships of SERPINE1

• The inclusion of neutralizing antibodies to TGF-beta in the co-culture medium blocked the observed increase in PAI-1 levels [17].
• SPARC stimulated the secretion of PAI-1 protein into the medium of subconfluent BAE cells, but not confluent BAE cells, in a dose- and time-dependent manner [18].
• Treating chondrocytes with IL-1 induced the expression of MMPs and downregulated TIMP-1 but stimulated both the expression of PAs and PAI-1 [19].

Other interactions of SERPINE1

• Since the induction of PAI-1 mRNA by SPARC was not blocked by cycloheximide, de novo protein synthesis was apparently not required for this stimulation [18].
• Both drugs inhibited the IL-1-induced mRNA expression of tPA, whereas expression of uPA was only mildly reduced by PSGAG, which also induced PAI-1 above IL-1 stimulated levels [19].
• OBJECTIVE: To determine the in vitro effects of several nonsteroidal antiinflammatory drugs on the IL-1 altered expression and activity of tPA, uPA and PAI-1 by articular chondrocytes [20].
• Kinetic analyses showed that anhydrotrypsin had little or no ability to compete with trypsin for binding to alpha 1-proteinase inhibitor (alpha 1PI), plasminogen activator inhibitor 1 (PAI-1), antithrombin (AT), or AT-heparin complex when present at up to a 100-fold molar excess over trypsin [21].
• The endotoxin-induced PAI from both cell types was not immunoprecipitated by incubation with IgG directed against the endothelial-type inhibitor, PAI-1, or antiserum directed against the placental-type inhibitor, PAI-2 [22].

Analytical, diagnostic and therapeutic context of SERPINE1

• The level of plasminogen activator inhibitor 1 (PAI-1) was also evaluated by Northern blotting and protein radiolabeling [13].
• This protein was identified as type 1 plasminogen activator inhibitor (PAI-1) on Western blots with anti-PAI-1 antiserum [18].
• Both control and treated cells produced multiple forms of PA, as evaluated by SDS-PAGE zymography, and a single form of PAI, as evidenced by reverse fibrin autography [23].
• By in situ hybridization, we demonstrate that the increase in PAI-1 mRNA is localized to cells at the edge of a wounded BME or BAE cell monolayer [24].
• PGD2 and PAI-1 levels were determined by radio- and enzyme-immunoassay, respectively [10].

References