Enhanced in Vitro Proliferation of Aortic Endothelial Cells from Plasminogen Activator Inhibitor-1-deficient Mice

Ploplis, Victoria A.; Balsara, Rashna D.; Sandoval-Cooper, Mayra J.; Yin, Zhi Jun; Batten, Jennifer; Modi, Nayan; Gadoua, Daniel; Donahue, Deborah L.; Martin, James A.; Castellino, Francis J.

doi:10.1074/jbc.m307297200

Cited by 49 publications

(48 citation statements)

References 28 publications

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“…Their observation of decreased neointimal formation after injury when PAI-1 expression was restored with adenoviral gene transfer 29 is consistent with our previous observation that increased expression of PAI-1 inhibits VSMC contribution to neointimal formation presumably by inhibiting migration. 8 Differing effects of PAI-1 on the in vitro proliferation of aortic endothelial cells 33 and VSMCs 34 are likely to be a reflection of differences in cell type, culture conditions, genotypes, and experimental design. Nevertheless, these results are consistent with the observation that increased intracellular expression PAI-1 promotes proliferation of VSMCs.…”

Section: Discussionmentioning

confidence: 99%

Augmentation of Proliferation of Vascular Smooth Muscle Cells by Plasminogen Activator Inhibitor Type 1

Chen

Budd

Kelm

et al. 2006

ATVB

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Objective-Proliferation of vascular smooth muscle cells (VSMCs) contributes to restenosis after coronary intervention.We have shown previously that increased expression of plasminogen activator inhibitor type 1 (PAI-1) limits VSMC apoptosis. Because apoptosis and proliferation appear to be linked, we sought to determine whether increased PAI-1 would affect VSMC proliferation. Methods and Results-VSMCs were explanted from control and transgenic mice (SM22-PAI ϩ ) in which VSMC expression of PAI-1 was increased. Increased growth of SM22-PAI ϩ -VSMCs (2.3Ϯ0.4-fold) reflected, at least partially, increased proliferation. Greater expression of FLICE-like inhibitory protein (FLIP; 2.7-fold) and its cleaved active form were seen in SM22-PAI ϩ -VSMCs. The balance between caspase-8 and FLIP favored proliferation in SM22-PAI ϩ -VSMCs. Increased expression of NF-B and activation of extracellular signal-regulated kinase (ERK) were demonstrated in SM22-PAI ϩ -VSMCs (foldϭNF-Bϭ2.2Ϯ0.1, foldϭphosphorylated-ERKϭ1.6Ϯ0.1). Results were confirmed when expression of PAI-1 was increased by transfection. Inhibition of NF-B and ERK attenuated proliferation in SM22-PAI ϩ -VSMCs. Increased expression of PAI-1 promoted proliferation when VSMCs were exposed to tumor necrosis factor (TNF). Conclusions-Increased expression of PAI-1 is associated with greater activity of FLIP that promotes VSMC proliferation through NF-B and ERK. Thus, when vascular wall expression of PAI-1 is increased, restenosis after coronary intervention is likely to be potentiated by greater proliferation of VSMC and resistance to apoptosis.

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Section: Discussionmentioning

confidence: 99%

Augmentation of Proliferation of Vascular Smooth Muscle Cells by Plasminogen Activator Inhibitor Type 1

Chen

Budd

Kelm

et al. 2006

ATVB

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“…Conversely, looking at PAI-1 levels, both hypoxia-induced PAI-1 expression [19] and nerve growth factor-induced PAI-1 expression [20] can be inhibited by PI3K inhibitors. A link between PAI-1 and phosphorylated Akt was recently demonstrated in aortic endothelial cells from the PAI-1 knockout mouse, which showed increased phosphorylated Akt levels compared to wild-type aortic endothelial cells [21]. Furthermore, both insulin-like growth factor-1 (IGF-1) and insulin modulate expression of uPA and PAI-1 through PI3K/Akt in breast cancer cells and in adipocytes [22,23].…”

Section: Introductionmentioning

confidence: 99%

Phosphatidylinositol 3-kinase/Akt regulates the balance between plasminogen activator inhibitor-1 and urokinase to promote migration of SKOV-3 ovarian cancer cells

Whitley

Beaulieu

Carter

et al. 2007

Gynecologic Oncology

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Objectives-Increased levels of urokinase-type plasminogen activator (uPA) are associated with shortened overall survival in ovarian cancer patients. Additionally, elevated levels of the serine protease inhibitor (serpin), plasminogen activator inhibitor-1 (PAI-1), a uPA inhibitor, have also been correlated with an unfavorable prognosis in ovarian cancer. Therefore, it is critical to understand the signaling pathways that regulate PAI-1 and uPA expression in cancer cell migration-invasion.Methods-We studied the PI3K/Akt, Rho kinase/ROCK, p38 MAPK and MEK pathways and their modulation of PAI-1 and uPA expression and wound-induced cell migration in SKOV-3 ovarian cancer cells. The PI3K/Akt pathway was further examined using pharmacological inhibitors (LY294002 and wortmannin), Akt siRNA, constitutively active Akt adenovirus and treatment with IGF-1/insulin in the SKOV-3 cells.Results-The PI3K/Akt pathway negatively regulates PAI-1 expression and positively correlates with migratory abilities and uPA expression in SKOV-3 cells. A reduction in active Akt results in an increase in PAI-1 expression coupled with a decrease in uPA expression to ultimately result in reduced cell migration and invasion. By contrast, an increase in Akt activity reduces PAI-1 expression and results in an increase in SKOV-3 wound-induced cell migration. Furthermore, IGF-1 and insulin stimulated SKOV-3 migration by altering the balance between uPA and PAI-1 to favor uPA, and the enhanced migration was attenuated by treatment with LY294002 indicating PI3K/Akt in this pathway. Conclusions-These results suggest an overall ovarian tumor-protective role for PAI-1, and that the PI3K/Akt signaling pathway regulates the ratio of PAI-1:uPA to either increase or decrease cell migration.

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“…PAI-1 is an essential target of p53, and both are necessary for the induction of replicative senescence of normal fibroblasts, which is associated with down-regulation of the growthpromoting Akt kinase pathway (43,49). The restoration of the Akt pathway in PAI-1 -deficient fibroblast and endothelial cells may allow these cells to escape growth arrest or senescence (43,59,60). In conclusion, through a rigorous semiquantitative RT-PCR screening approach, we showed that both NO-induced apoptosis and the up-regulation of the serpins maspin and PAI-1 are dependent on p53.…”

Section: Discussionmentioning

confidence: 93%

Focused PCR Screen Reveals p53 Dependence of Nitric Oxide-Induced Apoptosis and Up-Regulation of Maspin and Plasminogen Activator Inhibitor-1 in Tumor Cells

Lim

Hung

Porter

2009

Molecular Cancer Research

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We investigated p53-dependent gene expression in nitric oxide (NO)-induced apoptosis of two tumor cell types. Seventy-seven putative p53-regulated genes were screened for NO-mediated expression changes. Twenty-four genes were up-regulated and three genes were down-regulated significantly by NO in human neuroblastoma cells. Genes known to be involved in apoptosis, which were up-regulated by z2-fold, included FAS, CASP-1, BIK, PUMA, DR4 and the serpins maspin (SERPINB5), and plasminogen activator inhibitor-1 (PAI-1). Real-time PCR confirmed maspin and PAI-1 mRNAs exhibited the greatest NO-induced induction, which occurred in a p53-dependent manner. The substantial NO-mediated up-regulation of these serpins mRNAs correlated with large increases in their protein levels, which occurred before or coinciding with apoptosis. p53-deficient neuroblastoma cells were largely resistant to NO killing and showed much reduced maspin and PAI-1 mRNA and protein levels after NO treatment. p53 was activated by NO mainly in the nuclei of neuroblastoma cells. p53 À/À HCT116 colon carcinoma cells were strongly resistant to NO-induced apoptosis and failed to up-regulate maspin and PAI-1 (in contrast to p53 +/+ HCT116 cells). Our results suggest that both apoptosis and induction of the two serpins by NO require the transcriptional activity of p53. Because maspin is a tumor suppressor and PAI-1 can promote senescence and regulate cell death, it will now be worth investigating whether their p53-mediated expression contributes to the NO-induced p53-dependent death of tumor cells. (Mol Cancer Res 2009;7(1):55 -66)

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Enhanced in Vitro Proliferation of Aortic Endothelial Cells from Plasminogen Activator Inhibitor-1-deficient Mice

Cited by 49 publications

References 28 publications

Augmentation of Proliferation of Vascular Smooth Muscle Cells by Plasminogen Activator Inhibitor Type 1

Augmentation of Proliferation of Vascular Smooth Muscle Cells by Plasminogen Activator Inhibitor Type 1

Phosphatidylinositol 3-kinase/Akt regulates the balance between plasminogen activator inhibitor-1 and urokinase to promote migration of SKOV-3 ovarian cancer cells

Focused PCR Screen Reveals p53 Dependence of Nitric Oxide-Induced Apoptosis and Up-Regulation of Maspin and Plasminogen Activator Inhibitor-1 in Tumor Cells

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