Regulation of murine type 1 plasminogen activator inhibitor gene expression in vivo. Tissue specificity and induction by lipopolysaccharide, tumor necrosis factor-alpha, and transforming growth factor-beta.

Sawdey, M.; Loskutoff, David J.

doi:10.1172/jci115440

Cited by 397 publications

(292 citation statements)

References 52 publications

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“…PAI-1 is a serine protease inhibitor known to bind and inactivate both tissue-type and urokinase-type plasminogen activators (tPA and uPA), respectively . PAI-1 is found in low levels in the adult brain (Sawdey and Loskutoff, 1991), but its expression can be upregulated in astrocytes by stimulation with TGF-β1 and plasminogen (Datto et al, 1995;Buisson et al, 1998). Intravenous tPA has been used to treat acute stroke because of its thrombolytic activity and its ability to restore circulation to the brain (Hacke et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Lithium inhibits Smad3/4 transactivation via increased CREB activity induced by enhanced PKA and AKT signaling

Liang¹,

Wendland²,

Chuang³

2008

Molecular and Cellular Neuroscience

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Smad proteins are intracellular transducers for transforming growth factor-β (TGF-β signaling and play a critical role in differentiation, tissue repair and apoptosis of the central nervous system. Both TGF-β and its regulated gene, plasminogen activator inhibitor type-1 (PAI-1), have been implicated in the etiology and progression of neurodegenerative diseases and mood disorders. We previously reported that GSK-3β protein depletion suppresses Smad3/4-dependent gene transcription and causes a reduction in PAI-1 expression. Here, we provide evidence that lithium, the drug for the treatment and prophylaxis of bipolar disorder, inhibits Smad-dependent signaling by regulating cAMP-protein kinase A (PKA), AKT-glycogen synthase kinase-3β (GSK-3β), and CRE-dependent signaling pathways in neuron-enriched cerebral cortical cultures of rats. We demonstrate that lithium-induced activation of these pathways inhibits Smad3/4-dependent gene transcription through an increase in pCREB Ser133 protein levels, an enhanced interaction between pCREB Ser133 and p300/CBP, which causes Smad3/4-p300/CBP complex disruption and transcriptional suppression of Smad3/4-dependent genes. Therapeutic implications of our findings are discussed.

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Section: Discussionmentioning

confidence: 99%

Lithium inhibits Smad3/4 transactivation via increased CREB activity induced by enhanced PKA and AKT signaling

Liang¹,

Wendland²,

Chuang³

2008

Molecular and Cellular Neuroscience

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Section: Adipose Tissue As a Source Of Pai-1 In Obesitymentioning

confidence: 99%

“…13 The expression of TNF-␣ by adipose cells, particularly in the context of obesity, may interfere with certain aspects of insulin signaling, such as the tyrosine kinase activity of the insulin receptor, and thus contribute to insulin resistance. Interestingly, TNF-␣ is known to stimulate PAI-1 biosynthesis by a variety of cultured cells and by many murine tissues in vivo, 3,4,15 and administration of TNF-␣ to lean mice significantly increased PAI-1 mRNA in the adipocytes, adventitial cells, and vascular smooth muscle cells in the adipose tissues (Reference 9; Figs 1 and 2, compare panels A and C). This pattern is similar to the pattern of PAI-1 mRNA observed in the adipose tissues of obese mice (Figs 1 and 2, compare panels B and C).…”

mentioning

confidence: 99%

“…Initial clues for such a hypothesis came from the observation that the adipose tissue of the mouse contained relatively high levels of PAI-1 mRNA. 15 Moreover, clinical studies demonstrated that weight loss due to surgical treatment, diet, etc, significantly reduced plasma PAI-1 levels in obese humans. findings were noteworthy not only because adipose tissue was known to secrete a variety of proteins into blood 13,18 but also because in obese animals, the size and number of adipocytes and thus, the amount of adipose tissue mass, typically increases several-fold.…”

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confidence: 99%

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The Adipocyte and Hemostatic Balance in Obesity

Loskutoff

Samad

1998

ATVB

262

159

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P lasminogen activator inhibitor 1 is the primary physiological inhibitor of plasminogen activation in vivo, and elevations in plasma PAI-1 appear to compromise normal fibrin clearance mechanisms and promote thrombosis. PAI-1 is dramatically upregulated in obesity, a complex condition associated with increased risk for myocardial infarction, accelerated atherosclerosis, hypertension, glucose intolerance, insulin resistance, hyperinsulinemia, and NIDDM. In spite of the apparent link between elevated PAI-1 levels and thrombotic disease, little is known about the origin of this plasma inhibitor in obesity/NIDDM or about the signals that control its biosynthesis. Potential insights into the underlying molecular events have come from recent studies of genetically obese mice and of cultured adipocytes. These studies are reviewed here.* They emphasize the key role played by the adipocyte, a cell whose numbers, size, and metabolic activity are grossly altered in obesity/NIDDM. They also suggest that multiple cytokines, hormones, and growth factors may be involved, and they raise the possibility that the abnormal expression of other hemostatic genes by adipocytes in obesity/NIDDM may also contribute to the cardiovascular complications of this disorder. In this regard, our preliminary studies indicate that TF gene expression is elevated in the adipose tissues of the obese mouse. Properties of PAI-1PAI-1 appears to be the primary physiological inhibitor of plasminogen activation in blood, since it is the only PAI found complexed with single-chain tissue-type PA in carefully collected human plasma, and the second-order rate constant for its interaction with tissue-type PA and urokinase-type PA (Ϸ3.5ϫ10 7 [mol/L] Ϫ1 ⅐ s Ϫ1 ) is at least two orders of magnitude higher than that of other PAIs. [1][2][3][4] The normal concentration of PAI-1 protein in human plasma ranges from 6 to 80 ng/mL with a geometric mean at 24 ng/mL, whereas that of tissuetype PA is 5 to 10 ng/mL. Abnormalities in the concentration of PAI-1 are frequently associated with vascular disease. For example, the inhibitor is elevated in a variety of thrombotic conditions, including myocardial infarction and deep venous thrombosis. Elevated PAI-1 also correlates with thrombosis in animal models, and transgenic mice that overexpress PAI-1 have been reported to develop venous thrombosis. 5 On the other hand, the absence of PAI-1 in humans leads to life-long bleeding problems presumably resulting from the development of a hyperfibrinolytic state, and disruption of the PAI-1 gene in mice is also associated with a mild hyperfibrinolytic state as manifested by increased resistance to endotoxin-induced thrombosis. 5 Finally, neutralizing plasma PAI-1 activity with specific antibodies or by the use of PAI-1 inhibitors 4,6 enhances spontaneous or tissue-type PA-mediated thrombolysis. These observations emphasize that imbalances in the PA/PAI-1 ratio are likely to promote either thrombosis or bleeding. As summarized in the next section, this balance is severely disturbed ...

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“…PAI-1 or CEP promoter activity did not increase in response to TNFα to levels as high as those reported previously. 19,20 These observations may be explained by the possibility that DNA fragments used in this study may lack the TNFα responsive elements located upstream of the fragment, although one TNFα responsive element does reside in this fragment. 21,22 Based upon data shown in Table 1, the CEP promoter appeared to be 14-fold stronger than the PAI-1 promoter, comparable to the CAG promoter, and had similar responses to TGFβ1 and TNFα with the PAI-1 promoter.…”

Section: Activities and Properties Of Enhanced Pai-1 Promotermentioning

confidence: 90%

Recombinant adeno-associated virus vector-transduced vascular endothelial cells express the thrombomodulin transgene under the regulation of enhanced plasminogen activator inhibitor-1 promoter

et al. 2001

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Regulation of murine type 1 plasminogen activator inhibitor gene expression in vivo. Tissue specificity and induction by lipopolysaccharide, tumor necrosis factor-alpha, and transforming growth factor-beta.

Cited by 397 publications

References 52 publications

Lithium inhibits Smad3/4 transactivation via increased CREB activity induced by enhanced PKA and AKT signaling

Lithium inhibits Smad3/4 transactivation via increased CREB activity induced by enhanced PKA and AKT signaling

The Adipocyte and Hemostatic Balance in Obesity

Recombinant adeno-associated virus vector-transduced vascular endothelial cells express the thrombomodulin transgene under the regulation of enhanced plasminogen activator inhibitor-1 promoter

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