Disease relevance of Serpine1

• It was shown that the induction of PAI-1 mRNA and protein expression by insulin and mild hypoxia could be repressed by the PI3K inhibitor wortmannin [1].
• To determine the molecular mechanisms involved in the basal expression of the rat PAI-1 gene, we have analyzed the cis-acting sequences and the trans-acting factors involved in the transcription of this gene in the HTC rat hepatoma cell line [2].
• Different doses of 33H1F7 were infused to rats for 30 min and the dose which inactivates rapidly and totally active rat PAI-1 (300 microg/kg/min) was selected to be tested on the thrombosis model [3].
• Transforming growth factor beta (TGF beta) treatment of rat osteoblast-rich calvarial cells or of the clonal osteogenic sarcoma cells, UMR 106-01, resulted in dose-dependent inhibition of plasminogen activator (PA) activity, and increased production of 3.2 kb mRNA and protein for PA inhibitor -1 (PAI-1) [4].
• Hepatic stellate cells are an important source of PAI-1 during liver fibrosis [5].

Psychiatry related information on Serpine1

• MAIN OUTCOME MEASURE(S): Peritoneal fluid was analyzed for PA, PAI, MMP, and MMPI activities [6].

High impact information on Serpine1

• In fibrotic renal disease, elevated TGF-beta and angiotensin II lead to increased plasminogen activator inhibitor type 1 (PAI-1) [7].
• Further characterization of vasoactive peptide effects on PAI expression revealed that AII stimulated a 44.8 +/- 25.2-fold and a 12.4 +/- 3.2-fold increase in PAI-2 mRNA in RME cells and rat aortic smooth muscle cells (RASMC), respectively [8].
• METHODS: PAI-1 synthesis of liver cells at different time points of primary culture was studied by immunoprecipitation of endogenously labeled proteins followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and by Northern blotting [9].
• Transforming growth factor beta 1, tissue plasminogen activator, and dexamethasone increased PAI-1 production in HSCs [9].
• RESULTS: Among the various types of liver cells, PAI-1 protein and specific transcripts were present in HSCs and endothelial cells, and no major PAI-1 synthesis was detected in Kupffer cells and hepatocytes [9].

Chemical compound and disease context of Serpine1

• Incubation of HTC rat hepatoma cells with the synthetic glucocorticoid dexamethasone rapidly inhibits plasminogen activator (PA) activity and reveals the presence of a specific PA inhibitor (PAI-1) [10].
• PPAR gamma beneficial effects are independent of insulin/glucose effects and are associated with regulation of glomerular cell proliferation, hypertrophy, and decreased PAI-1 and TGF-beta expression [11].
• Taurine significantly reduced plasma LPO, glomerular PAI-1 expression, glomerular volume, fractional mesangial area, and proteinuria in streptozotocin-induced diabetic rats [12].
• In the repair protocol, clopidogrel significantly limited aneurysm formation and fibrinogen deposition, as well as glomerular matrix expansion, TGF-beta 1, fibronectin, and PAI-1 expression [13].
• The increase in plasma PAI activity during hypothyroidism may thus not be a direct effect of the thyroid hormone, but an indirect one through some other, possibly cholesterol related, component [14].

Biological context of Serpine1

• Mutation of the hypoxia response elements (HRE-1 and HRE-2) in rat PAI-1 promoter, which could bind hypoxia inducible factor-1 (HIF-1), abolished the induction of PAI-1 by insulin and PKB [1].
• In the present study, we observed that the plasminogen activator inhibitor-1 (PAI-1) levels in serum and its gene expression in adipose tissue were up-regulated in aged OLETF rats, model animals of obese type 2 diabetes [15].
• The up-regulation of PAI-1 was also observed by incubating the cells in high glucose medium (30 mm, 48 h) [15].
• The expression of fusion genes containing progressive 5' deletions of the rat PAI-1 promoter linked to the chloramphenicol acetyltransferase reporter gene were analyzed in transient transfection experiments in HTC cells [2].
• The complete nucleotide sequence of the rat PAI-1 gene, including 2.4 kb of 5'- and 1 kb of 3'-flanking DNA, has been determined [16].

Anatomical context of Serpine1

• These results suggest that cellular carbonyl stress induced by AGEs or HNE may stimulate PAI-1 synthesis in and release from adipose tissues through ROS formation [15].
• Stimulation of primary white adipocytes by either AGE or HNE resulted in the elevation of PAI-1 in culture medium and at mRNA levels [15].
• In vitro, supernatants, cytosols, and membranes of renal proximal tubular cells in primary cultures had no detectable uPA activity, and lovastatin (0.1 to 10 microM) induced an increase in tPA and a decrease in PAI-1 activities and antigens [17].
• In liver cell cultures, Kupffer cells, hepatocytes, and especially stellate cells, expressed PAI-1 [5].
• PAI-1 expression is required for epithelial cell migration in two distinct phases of in vitro wound repair [18].

Associations of Serpine1 with chemical compounds

• To study the mechanism of PAI-1 up-regulation, we examined the effect of advanced glycation end products (AGEs) and the product of lipid peroxidation (4-hydroxy-2-nonenal (HNE)), both of which are endogenously generated under carbonyl stress [15].
• Incubation with lovastatin (5 microM) of proximal tubules isolated from untreated rats induced an increase in tPA and uPA and a decrease in plasminogen activator inhibitor-1 (PAI-1) activities [17].
• C3 exoenzyme, an inhibitor of the geranylgeranylated-activated Rho protein, reproduced the effect of lovastatin on tPA and PAI- activity and blocked its reversion by GGPP [17].
• Plasminogen activator inhibitor-1 (PAI-1) expression is directly regulated by clock genes, while angiotensin II modulates both PAI-1 and clock gene expression [19].
• Candesartan treatment decreased cardiac PAI-1 expression only in the dark in WKY rats but throughout the day in SHR [19].

Physical interactions of Serpine1

• In addition to the free pool of tPA, a large portion of tPA is complexed to PAI-1 and is therefore functionally inactive [20].
• Electrophoretic mobility shift assays with radiolabeled oligonucleotides containing the two putative Sp1-binding sites from PAI-1 promoter and nuclear extracts from RASM cells revealed that glucose treatment markedly changed the mobility pattern of the major protein-DNA complexes [21].

Regulatory relationships of Serpine1

• Pharmacologic inhibition of keratinocyte MEK signaling effectively ablated scrape-induced PAI-1 mRNA expression but failed to attenuate wound-associated increases in cellular PAI-1 protein levels soon after monolayer injury [18].
• Moreover, purified TGF beta-1 produces a Schwann cell morphology alteration and decreases the secretion of tissue-type plasminogen activator (tPA) and enhances the secretion of plasminogen activator inhibitor (PAI) by Schwann cells [22].
• In conclusion, G-protein-coupled receptor agonist-induced PAI-1 expression is partially mediated through JNK activation [23].
• A reverse fibrin zymogram indicated that PAI activity was greatly enhanced in TGF beta-treated CM [24].
• This stimulation is specifically mediated by TxA2 (thromboxane prostanoid, TP) receptors, since U-46619 also stimulates PAI-1 expression in cells that are transfected with TP receptors, and this stimulation of PAI-1 production is completely blocked by the TxA2 receptor antagonist, SQ-29,548 [25].

Other interactions of Serpine1

• Systolic blood pressure (SBP) was measured monthly up to 8 months of age, when the animals were killed; then, CG and AG were excised and processed for light microscopy and immunohistochemistry (TGF-beta 1, PAI-1 and protein S100) [26].
• Western analysis was performed to detect protein expression of PAI-1, uPA and uPAR [5].
• Egr-1 and PAI-1 were specifically induced during the first few hours in the hyper-perfused lobes following PBL and PH [27].
• Reactive oxygen species modulate HIF-1 mediated PAI-1 expression: involvement of the GTPase Rac1 [28].
• Northern analysis confirmed upregulation of three of these genes, PAI-1, P2X4, and P15INK4B [29].

Analytical, diagnostic and therapeutic context of Serpine1

• S-phase-specific mRNA-levels of H2B-histone protein (H2B), as well as expression analysis of Egr-1, PAI-1 and PRL-1 were examined by Northern blot experiments [27].
• We examined the expression of PAI-1, uPA, and uPAR mRNAs through the use of in situ hybridization and that of type IV collagen by means of immunohistochemical methods [30].
• Western blots showed increased PAI-1 in grafts from the LPSN group compared with LXSN and NO groups [31].
• METHODS AND RESULTS: Guinea pig-to-rat aortic xenografts were seeded with syngeneic Fischer 344 rat smooth muscle cells retrovirally transduced with the rat PAI-1 gene (LPSN group) or the vector alone (LXSN group) [31].
• PAI-1 mRNA expression was noted at 6 h, peaking at 1 day, and although falling thereafter, remained higher than that of the control group through Day 17 [32].

References