11 results on '"Bonello, Steve"'
Search Results
2. The expression of the NADPH oxidase subunit p22phox is regulated by a redox-sensitive pathway in endothelial cells
- Author
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Djordjevic, Talija, Pogrebniak, Alexej, BelAiba, Rachida S., Bonello, Steve, Wotzlaw, Christoph, Acker, Helmut, Hess, John, and Görlach, Agnes
- Published
- 2005
- Full Text
- View/download PDF
3. Redox-sensitive regulation of the HIF pathway under non-hypoxic conditions in pulmonary artery smooth muscle cells
- Author
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BelAiba, Rachida S., Djordjevic, Talija, Bonello, Steve, Flügel, Daniela, Hess, John, Kietzmann, Thomas, and Görlach, Agnes
- Published
- 2004
4. The Serum- and Glucocorticoid-Inducible Kinase Sgk-1 Is Involved in Pulmonary Vascular Remodeling.
- Author
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BelAiba, Rachida S., Djordjevic, Talija, Bonello, Steve, Artunc, Ferruh, Lang, Florian, Hess, John, and Görlach, Agnes
- Published
- 2006
- Full Text
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5. Steve Bonello from Malta with ‘Ways of Seeing’.
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Bonello, Steve
- Subjects
- *
POPULISM , *POLITICAL doctrines , *DEMOCRACY - Published
- 2018
6. The hypoxia-inducible factor-2alpha is stabilized by oxidative stress involving NOX4.
- Author
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Diebold I, Flügel D, Becht S, Belaiba RS, Bonello S, Hess J, Kietzmann T, and Görlach A
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- Animals, Ascorbic Acid metabolism, Ascorbic Acid pharmacology, Basic Helix-Loop-Helix Transcription Factors genetics, Blotting, Western, Cell Line, Tumor, Cell Proliferation drug effects, Cells, Cultured, Humans, Hydrogen Peroxide pharmacology, Iron metabolism, NADPH Oxidase 4, NADPH Oxidases genetics, Oxidative Stress drug effects, Oxidative Stress genetics, Rats, Reactive Oxygen Species metabolism, Thrombin pharmacology, Von Hippel-Lindau Tumor Suppressor Protein genetics, Von Hippel-Lindau Tumor Suppressor Protein metabolism, Basic Helix-Loop-Helix Transcription Factors metabolism, NADPH Oxidases metabolism, Oxidative Stress physiology
- Abstract
The hypoxia-inducible factor-2alpha (HIF-2alpha) contributes to the vascular response to hypoxia. Hypoxia inhibits prolyl hydroxylation of the N-terminal transactivation domain (N-TAD), thus preventing binding of the von Hippel-Lindau protein (pVHL) and proteasomal degradation; additionally, hypoxia inhibits asparagyl hydroxylation of the C-TAD, thus diminishing cofactor recruitment. Reactive oxygen species (ROS) derived from NADPH oxidases (NOXs) have been shown to control vascular functions and to promote vascular remodeling. However, whether HIF-2alpha, ROS, and NOXs are linked under such nonhypoxic conditions is unclear. We found that activation of NOX4 by thrombin or H(2)O(2) increased HIF-2alpha protein because of decreased pVHL binding in pulmonary artery smooth muscle cells (PASMCs). Thrombin, H(2)O(2), and NOX4 overexpression increased HIF-2alpha N-TAD and C-TAD activity, which was prevented by ascorbate treatment or mutation of the hydroxylation sites in the TADs. HIF-2alpha also mediated induction of plasminogen activator inhibitor-1 and the proliferative response to thrombin, H(2)O(2), or NOX4 overexpression. Thus, ROS derived from NOX4 in response to thrombin stabilize HIF-2alpha by preventing hydroxylation of the N- and C-TAD, thus allowing formation of transcriptionally active HIF-2alpha, which promotes PASMC proliferation. Together, these findings present the first evidence that HIF-2alpha is critically involved in the ROS-regulated vascular remodeling processes.
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- 2010
- Full Text
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7. The 'PAI-1 paradox' in vascular remodeling.
- Author
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Diebold I, Kraicun D, Bonello S, and Görlach A
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- Animals, Atherosclerosis metabolism, Cardiovascular Diseases genetics, Cardiovascular Diseases pathology, Cell Proliferation, Endothelium, Vascular injuries, Endothelium, Vascular pathology, Humans, Hypertension, Pulmonary, Mice, Mice, Knockout, Muscle, Smooth, Vascular injuries, Muscle, Smooth, Vascular pathology, Plasminogen Activator Inhibitor 1 genetics, Pulmonary Artery metabolism, Cardiovascular Diseases metabolism, Endothelium, Vascular metabolism, Muscle, Smooth, Vascular metabolism, Plasminogen Activator Inhibitor 1 metabolism, Signal Transduction
- Abstract
Vascular remodelling is a complex phenomenon associated with restructuring of the vessel wall as a consequence of disruption of vascular homeostasis. Alterations of the vascular wall have been linked to a variety of cardiovascular disorders including atherosclerosis, vascular injury and pulmonary hypertension. Plasminogen activator inhibitor-1 (PAI-1) is a member of the serpin (serine proteinase inhibitor) family and acts as an important inhibitor of fibrinolysis by interfering with the plasminogen system. In addition to its anti-fibrinolytic effects, PAI-1 appears to modulate cellular responses linked to vascular remodelling. Since PAI-1 levels have been shown to be altered in various disorders associated with vascular remodelling of the systemic and pulmonary vascular bed, this serpin may play a pivotal role in the pathogenesis of these diseases.
- Published
- 2008
8. The cross-talk between NF-kappaB and HIF-1: further evidence for a significant liaison.
- Author
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Görlach A and Bonello S
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- Cell Hypoxia, Humans, Hypoxia-Inducible Factor 1 genetics, Models, Biological, NF-kappa B genetics, Reactive Oxygen Species metabolism, Tumor Necrosis Factor-alpha metabolism, Hypoxia-Inducible Factor 1 metabolism, NF-kappa B metabolism, Signal Transduction
- Abstract
HIF-1 (hypoxia-inducible factor-1) has been shown to essentially control the cellular response to hypoxia. Hypoxia stabilizes the inducible alpha-subunit, preventing post-translational hydroxylation and subsequent degradation via the proteasome. In recent years, clear evidence has emerged that HIF-1alpha is also responsive to many stimuli under normoxic conditions, including thrombin, growth factors, vasoactive peptides, insulin, lipopolysaccharide and cytokines such as TNF-alpha (tumour necrosis factor-alpha), and in many cases reactive oxygen species are involved. One important mechanism underlying these responses is the transcriptional regulation of HIF-1alpha by the redox-sensitive transcription factor NF-kappaB (nuclear factor kappaB), which binds at a distinct element in the proximal promoter of the HIF-1alpha gene. More recently, NF-kappaB binding to this site in the HIF-1alpha promoter has been shown also under hypoxic conditions. Thus these two major pathways regulating the responses to inflammation and oxidative stress on the one hand, and hypoxia on the other hand, appear to be intimately linked. In this issue of the Biochemical Journal, a study by van Uden et al. has supported these findings further, in which they have confirmed the binding of several proteins of the NF-kappaB family at the previously identified consensus site in the HIF-1alpha promoter and shown that TNF-alpha can also transcriptionally induce HIF-1alpha by this previously described pathway. The identification of HIF-1alpha as a target gene of NF-kappaB will have important implications for a variety of disorders related to hypoxia-ischaemia and/or inflammation and oxidative stress.
- Published
- 2008
- Full Text
- View/download PDF
9. Hypoxia up-regulates hypoxia-inducible factor-1alpha transcription by involving phosphatidylinositol 3-kinase and nuclear factor kappaB in pulmonary artery smooth muscle cells.
- Author
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Belaiba RS, Bonello S, Zähringer C, Schmidt S, Hess J, Kietzmann T, and Görlach A
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- Animals, Arteries metabolism, Base Sequence, Cells, Cultured, Humans, Hypoxia genetics, Hypoxia-Inducible Factor 1, alpha Subunit genetics, Mice, Mice, Inbred C57BL, Proto-Oncogene Proteins c-akt, RNA, Messenger genetics, Signal Transduction, Hypoxia metabolism, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Myocytes, Smooth Muscle metabolism, NF-kappa B metabolism, Phosphatidylinositol 3-Kinases metabolism, Transcription, Genetic genetics, Up-Regulation genetics
- Abstract
The oxygen sensitive alpha-subunit of the hypoxia-inducible factor-1 (HIF-1) is a major trigger of the cellular response to hypoxia. Although the posttranslational regulation of HIF-1alpha by hypoxia is well known, its transcriptional regulation by hypoxia is still under debate. We, therefore, investigated the regulation of HIF-1alpha mRNA in response to hypoxia in pulmonary artery smooth muscle cells. Hypoxia rapidly enhanced HIF-1alpha mRNA levels and HIF-1alpha promoter activity. Furthermore, inhibition of the phosphatidylinositol 3-kinase (PI3K)/AKT but not extracellular signal-regulated kinase 1/2 pathway blocked the hypoxia-dependent induction of HIF-1alpha mRNA and HIF-1alpha promoter activity, suggesting involvement of a PI3K/AKT-regulated transcription factor. Interestingly, hypoxia also induced nuclear factor-kappaB (NFkappaB) nuclear translocation and activity. In line, expression of the NFkappaB subunits p50 and p65 enhanced HIF-1alpha mRNA levels, whereas blocking of NFkappaB by an inhibitor of nuclear factor-kappaB attenuated HIF-1alpha mRNA induction by hypoxia. Reporter gene assays revealed the presence of an NFkappaB site within the HIF-1alpha promoter, and mutation of this site abolished induction by hypoxia. In line, gel shift analysis and chromatin immunoprecipitation confirmed binding of p50 and p65 NFkappaB subunits to the HIF-1alpha promoter under hypoxia. Together, these findings provide a novel mechanism in which hypoxia induces HIF-1alpha mRNA expression via the PI3K/AKT pathway and activation of NFkappaB.
- Published
- 2007
- Full Text
- View/download PDF
10. Reactive oxygen species activate the HIF-1alpha promoter via a functional NFkappaB site.
- Author
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Bonello S, Zähringer C, BelAiba RS, Djordjevic T, Hess J, Michiels C, Kietzmann T, and Görlach A
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- Binding Sites, Cells, Cultured, Gene Expression Regulation, Humans, Hydrogen Peroxide pharmacology, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Myocytes, Smooth Muscle metabolism, NF-kappa B physiology, Plasminogen Activator Inhibitor 1 genetics, Pulmonary Artery cytology, RNA, Messenger metabolism, Thrombin pharmacology, Transcription, Genetic physiology, Hypoxia-Inducible Factor 1, alpha Subunit genetics, NF-kappa B metabolism, Promoter Regions, Genetic physiology, Reactive Oxygen Species metabolism
- Abstract
Objective: Reactive oxygen species have been implicated as signaling molecules modulating the activity of redox-sensitive transcription factors such as nuclear factor kappa B (NF-kappaB). Recently, the transcription factor hypoxia-inducible factor-1 (HIF-1), known to mediate gene expression by hypoxia, has been found to be also activated by nonhypoxic factors in a redox-sensitive manner. We therefore aimed to elucidate the link between these 2 important redox-sensitive transcription factors., Methods and Results: In pulmonary artery smooth muscle cells, reactive oxygen species generated either by exogenous H2O2 or by a NOX4-containing NADPH oxidase stimulated by thrombin activated or induced NF-kappaB and HIF-1alpha. The reactive oxygen species-mediated HIF-1alpha induction occurred on the transcriptional level and was dependent on NF-kappaB. Transfection experiments with wild-type or mutant HIF-1alpha promoter constructs revealed the presence of a yet unidentified NF-kappaB binding element. Gel shift analyses and chromatin immunoprecipitation verified binding of NF-kappaB to this site. Furthermore, reactive oxygen species enhanced expression of plasminogen activator inhibitor-1, which was prevented by dominant-negative IkappaB or mutation of the HIF-1 binding site within the plasminogen activator inhibitor-1 promoter., Conclusion: These findings show for the first time to our knowledge that reactive oxygen species directly link HIF-1alpha and NF-kappaB, implicating an important pathophysiological role of this novel pathway in disorders associated with elevated levels of reactive oxygen species.
- Published
- 2007
- Full Text
- View/download PDF
11. Human urotensin II is a novel activator of NADPH oxidase in human pulmonary artery smooth muscle cells.
- Author
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Djordjevic T, BelAiba RS, Bonello S, Pfeilschifter J, Hess J, and Görlach A
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- Antisense Elements (Genetics), Cell Division drug effects, Cell Division physiology, Cells, Cultured, Humans, Hypertension, Pulmonary metabolism, Membrane Transport Proteins genetics, Membrane Transport Proteins metabolism, Mitogen-Activated Protein Kinases metabolism, Muscle, Smooth, Vascular cytology, NADPH Oxidase 4, NADPH Oxidases genetics, Phosphoproteins genetics, Phosphoproteins metabolism, Plasminogen Activator Inhibitor 1 genetics, Plasminogen Activator Inhibitor 1 metabolism, Protein Serine-Threonine Kinases metabolism, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins c-akt, RNA, Messenger metabolism, Reactive Oxygen Species metabolism, Muscle, Smooth, Vascular drug effects, Muscle, Smooth, Vascular enzymology, NADPH Oxidases metabolism, Pulmonary Artery cytology, Urotensins pharmacology
- Abstract
Background: Human urotensin II (hU-II) is a potent vasoactive peptide possibly involved in pulmonary hypertension. Because the signaling mechanisms activated by this peptide in the pulmonary vasculature are largely unknown, we investigated the role of hU-II in the activation of NADPH oxidase and the control of redox-sensitive kinase pathways, expression of plasminogen activator inhibitor-1 (PAI-1), and proliferation in pulmonary artery smooth muscle cells (PASMCs)., Methods and Results: hU-II upregulated expression of the NADPH oxidase subunits p22phox and NOX4 and increased the levels of reactive oxygen species (ROS), which were abrogated by transfecting p22phox or NOX4 antisense vectors. p22phox and NOX4 also contributed to hU-II-induced activation of extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, and protein kinase B (Akt). Furthermore, hU-II increased the expression of PAI-1 and enhanced PASMC proliferation in an NADPH oxidase- and kinase-dependent manner., Conclusions: hU-II is a potent activator of ROS generation by NADPH oxidase in PASMCs, leading to redox-sensitive activation of mitogen-activated protein kinases and Akt and subsequently to enhanced PAI-1 expression and increased proliferation. These findings suggest that hU-II may play a novel role in pulmonary hypertension by promoting remodeling processes via activation of NADPH oxidases.
- Published
- 2005
- Full Text
- View/download PDF
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