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Article ; Online: Short symmetric and highly selective asymmetric first and second order gradient modulated offset independent adiabaticity (GOIA) pulses for applications in clinical MRS and MRSI.

Kumaragamage, Chathura / Coppoli, Anastasia / Brown, Peter B / McIntyre, Scott / Nixon, Terence W / De Feyter, Henk M / Mason, Graeme F / de Graaf, Robin A

Journal of magnetic resonance (San Diego, Calif. : 1997)

2022 Volume 341, Page(s) 107247

Abstract: Gradient modulated RF pulses, especially gradient offset independent adiabaticity (GOIA) pulses, are increasingly gaining attention for high field clinical magnetic resonance spectroscopy and spectroscopic imaging (MRS/MRSI) due to the lower peak ... ...

Abstract	Gradient modulated RF pulses, especially gradient offset independent adiabaticity (GOIA) pulses, are increasingly gaining attention for high field clinical magnetic resonance spectroscopy and spectroscopic imaging (MRS/MRSI) due to the lower peak B
MeSH term(s)	Brain/metabolism ; Heart Rate ; Magnetic Resonance Imaging/methods ; Phantoms, Imaging ; Signal Processing, Computer-Assisted
Language	English
Publishing date	2022-06-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1469665-4
ISSN	1096-0856 ; 1557-8968 ; 1090-7807 ; 0022-2364
ISSN (online)	1096-0856 ; 1557-8968
ISSN	1090-7807 ; 0022-2364
DOI	10.1016/j.jmr.2022.107247
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Article ; Online: Sphingolipids in inflammation: pathological implications and potential therapeutic targets.

Nixon, Graeme F

British journal of pharmacology

2009 Volume 158, Issue 4, Page(s) 982–993

Abstract: Sphingolipids are formed via the metabolism of sphingomyelin, a constituent of the plasma membrane, or by de novo synthesis. Enzymatic pathways result in the formation of several different lipid mediators, which are known to have important roles in many ... ...

Abstract	Sphingolipids are formed via the metabolism of sphingomyelin, a constituent of the plasma membrane, or by de novo synthesis. Enzymatic pathways result in the formation of several different lipid mediators, which are known to have important roles in many cellular processes, including proliferation, apoptosis and migration. Several studies now suggest that these sphingolipid mediators, including ceramide, ceramide 1-phosphate and sphingosine 1-phosphate (S1P), are likely to have an integral role in inflammation. This can involve, for example, activation of pro-inflammatory transcription factors in different cell types and induction of cyclooxygenase-2, leading to production of pro-inflammatory prostaglandins. The mode of action of each sphingolipid is different. Increased ceramide production leads to the formation of ceramide-rich areas of the membrane, which may assemble signalling complexes, whereas S1P acts via high-affinity G-protein-coupled S1P receptors on the plasma membrane. Recent studies have demonstrated that in vitro effects of sphingolipids on inflammation can translate into in vivo models. This review will highlight the areas of research where sphingolipids are involved in inflammation and the mechanisms of action of each mediator. In addition, the therapeutic potential of drugs that alter sphingolipid actions will be examined with reference to disease states, such as asthma and inflammatory bowel disease, which involve important inflammatory components. A significant body of research now indicates that sphingolipids are intimately involved in the inflammatory process and recent studies have demonstrated that these lipids, together with associated enzymes and receptors, can provide effective drug targets for the treatment of pathological inflammation.
MeSH term(s)	Animals ; Asthma/drug therapy ; Asthma/metabolism ; Ceramides/metabolism ; Humans ; Inflammation/metabolism ; Inflammatory Bowel Diseases/drug therapy ; Inflammatory Bowel Diseases/metabolism ; Lysophospholipids/metabolism ; Prostaglandin-Endoperoxide Synthases/metabolism ; Sphingolipids/metabolism ; Sphingosine/analogs & derivatives ; Sphingosine/metabolism
Chemical Substances	Ceramides ; Lysophospholipids ; Sphingolipids ; sphingosine 1-phosphate (26993-30-6) ; Prostaglandin-Endoperoxide Synthases (EC 1.14.99.1) ; Sphingosine (NGZ37HRE42)
Language	English
Publishing date	2009-06-25
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	80081-8
ISSN	1476-5381 ; 0007-1188
ISSN (online)	1476-5381
ISSN	0007-1188
DOI	10.1111/j.1476-5381.2009.00281.x
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Article ; Online: Phosphoprotein enriched in astrocytes (PEA)-15: a potential therapeutic target in multiple disease states.

Greig, Fiona H / Nixon, Graeme F

Pharmacology & therapeutics

2014 Volume 143, Issue 3, Page(s) 265–274

Abstract: Phosphoprotein enriched in astrocytes-15 (PEA-15) is a cytoplasmic protein that sits at an important junction in intracellular signalling and can regulate diverse cellular processes, such as proliferation and apoptosis, dependent upon stimulation. ... ...

Abstract	Phosphoprotein enriched in astrocytes-15 (PEA-15) is a cytoplasmic protein that sits at an important junction in intracellular signalling and can regulate diverse cellular processes, such as proliferation and apoptosis, dependent upon stimulation. Regulation of these processes occurs by virtue of the unique interaction of PEA-15 with other signalling proteins. PEA-15 acts as a cytoplasmic tether for the mitogen-activated protein kinases, extracellular signal-regulated kinase 1/2 (ERK1/2) preventing nuclear localisation. In order to release ERK1/2, PEA-15 requires to be phosphorylated via several potential pathways. PEA-15 (and its phosphorylation state) therefore regulates many ERK1/2-dependent processes, including proliferation, via regulating ERK1/2 nuclear translocation. In addition, PEA-15 contains a death effector domain (DED) which allows interaction with other DED-containing proteins. PEA-15 can bind the DED-containing apoptotic adaptor molecule, Fas-associated death domain protein (FADD) which is also dependent on the phosphorylation status of PEA-15. PEA-15 binding of FADD can inhibit apoptosis as bound FADD cannot participate in the assembly of apoptotic signalling complexes. Through these protein-protein interactions, PEA-15-regulated cellular effects have now been investigated in a number of disease-related studies. Changes in PEA-15 expression and regulation have been observed in diabetes mellitus, cancer, neurological disorders and the cardiovascular system. These changes have been suggested to contribute to the pathology related to each of these disease states. As such, new therapeutic targets based around PEA-15 and its associated interactions are now being uncovered and could provide novel avenues for treatment strategies in multiple diseases.
MeSH term(s)	Animals ; Apoptosis Regulatory Proteins ; Brain Diseases/metabolism ; Cardiovascular Diseases/metabolism ; Endocrine System Diseases/metabolism ; Humans ; Intracellular Signaling Peptides and Proteins/chemistry ; Intracellular Signaling Peptides and Proteins/metabolism ; Neoplasms/metabolism ; Phosphoproteins/chemistry ; Phosphoproteins/metabolism ; Protein Conformation
Chemical Substances	Apoptosis Regulatory Proteins ; Intracellular Signaling Peptides and Proteins ; PEA15 protein, human ; Phosphoproteins
Language	English
Publishing date	2014-03-20
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	194735-7
ISSN	1879-016X ; 0163-7258
ISSN (online)	1879-016X
ISSN	0163-7258
DOI	10.1016/j.pharmthera.2014.03.006
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Zs.A 1183: Show issues

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Article ; Online: An endogenous inhibitor of angiogenesis downregulated by hypoxia in human aortic valve stenosis promotes disease pathogenesis.

Lewis, Christopher T A / Mascall, Keith S / Wilson, Heather M / Murray, Fiona / Kerr, Keith M / Gibson, George / Buchan, Keith / Small, Gary R / Nixon, Graeme F

Journal of molecular and cellular cardiology

2022 Volume 174, Page(s) 25–37

Abstract: Aortic valve stenosis is the most common valve disease in the western world. Central to the pathogenesis of this disease is the growth of new blood vessels (angiogenesis) within the aortic valve allowing infiltration of immune cells and development of ... ...

Abstract	Aortic valve stenosis is the most common valve disease in the western world. Central to the pathogenesis of this disease is the growth of new blood vessels (angiogenesis) within the aortic valve allowing infiltration of immune cells and development of intra-valve inflammation. Identifying the cellular mediators involved in this angiogenesis is important as this may reveal new therapeutic targets which could ultimately prevent the progression of aortic valve stenosis. Aortic valves from patients undergoing surgery for aortic valve replacement or dilation of the aortic arch were examined both ex vivo and in vitro. We now demonstrate that the anti-angiogenic protein, soluble fms-like tyrosine kinase 1 (sFlt1), a non-signalling soluble receptor for vascular endothelial growth factor, is constitutively expressed in non-diseased valves. sFlt-1 expression was, however, significantly reduced in aortic valve tissue from patients with aortic valve stenosis while protein markers of hypoxia were simultaneously increased. Exposure of primary-cultured valve interstitial cells to hypoxia resulted in a decrease in the expression of sFlt-1. We further reveal using a bioassay that siRNA knock-down of sFlt1 in valve interstitial cells directly results in a pro-angiogenic environment. Finally, incubation of aortic valves with sphingosine 1-phosphate, a bioactive lipid-mediator, increased sFlt-1 expression and inhibited angiogenesis within valve tissue. In conclusion, this study demonstrates that sFlt1 expression is directly correlated with angiogenesis in aortic valves and the observed decrease in sFlt-1 expression in aortic valve stenosis could increase valve inflammation, promoting disease progression. This could be a viable therapeutic target in treating this disease.
MeSH term(s)	Humans ; Vascular Endothelial Growth Factor Receptor-1/genetics ; Vascular Endothelial Growth Factor Receptor-1/metabolism ; Vascular Endothelial Growth Factor A/metabolism ; Aortic Valve Stenosis/metabolism ; Aortic Valve/pathology ; Inflammation/pathology ; Hypoxia/metabolism
Chemical Substances	FLT1 protein, human (EC 2.7.10.1) ; Vascular Endothelial Growth Factor Receptor-1 (EC 2.7.10.1) ; Vascular Endothelial Growth Factor A
Language	English
Publishing date	2022-11-04
Publishing country	England
Document type	Journal Article
ZDB-ID	80157-4
ISSN	1095-8584 ; 0022-2828
ISSN (online)	1095-8584
ISSN	0022-2828
DOI	10.1016/j.yjmcc.2022.10.010
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Article ; Online: Phosphoprotein enriched in astrocytes (PEA)-15 is a novel regulator of adipose tissue expansion.

Verschoor, Pola J / Greig, Fiona H / Rochford, Justin J / Levate, Giovanni / Delibegovic, Mirela / Thompson, Dawn / Leeson-Payne, Alasdair / Dekeryte, Ruta / Banks, Ruth / Ramos, Joe W / Nixon, Graeme F

Scientific reports

2021 Volume 11, Issue 1, Page(s) 6949

Abstract: Excessive expansion of adipose tissue in obesity typically leads to overflow and accumulation of lipids in other tissues, causing fatty liver disease and atherosclerosis. The intracellular protein, phosphoprotein enriched in astrocytes (PEA)-15 has been ... ...

Abstract	Excessive expansion of adipose tissue in obesity typically leads to overflow and accumulation of lipids in other tissues, causing fatty liver disease and atherosclerosis. The intracellular protein, phosphoprotein enriched in astrocytes (PEA)-15 has been linked to metabolic disease but its role in lipid storage has not been examined. To delineate the role of PEA-15 in adipose tissue, we placed PEA-15
MeSH term(s)	3T3 Cells ; Adipocytes/metabolism ; Adipose Tissue/growth & development ; Adiposity/genetics ; Adiposity/physiology ; Animals ; Apoptosis Regulatory Proteins/genetics ; Apoptosis Regulatory Proteins/metabolism ; Astrocytes/metabolism ; Atherosclerosis/pathology ; Atherosclerosis/prevention & control ; Cell Line ; Diet, High-Fat ; Insulin Resistance/genetics ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Obesity/pathology ; Phosphoproteins/metabolism ; Triglycerides/blood
Chemical Substances	Apoptosis Regulatory Proteins ; Pea15 protein, mouse ; Phosphoproteins ; Triglycerides
Language	English
Publishing date	2021-03-26
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-021-86250-x
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Article ; Online: Phosphoprotein enriched in astrocytes (PEA)-15 is a novel regulator of adipose tissue expansion

Pola J. Verschoor / Fiona H. Greig / Justin J. Rochford / Giovanni Levate / Mirela Delibegovic / Dawn Thompson / Alasdair Leeson-Payne / Ruta Dekeryte / Ruth Banks / Joe W. Ramos / Graeme F. Nixon

Scientific Reports, Vol 11, Iss 1, Pp 1-

2021 Volume 14

Abstract: Abstract Excessive expansion of adipose tissue in obesity typically leads to overflow and accumulation of lipids in other tissues, causing fatty liver disease and atherosclerosis. The intracellular protein, phosphoprotein enriched in astrocytes (PEA)-15 ... ...

Abstract	Abstract Excessive expansion of adipose tissue in obesity typically leads to overflow and accumulation of lipids in other tissues, causing fatty liver disease and atherosclerosis. The intracellular protein, phosphoprotein enriched in astrocytes (PEA)-15 has been linked to metabolic disease but its role in lipid storage has not been examined. To delineate the role of PEA-15 in adipose tissue, we placed PEA-15−/− mice on a high fat diet. These mice developed increased body weight and greater white adipose tissue expansion compared to high fat diet-fed wild type mice. This was due to increased adipocyte cell size in PEA-15−/− mice consistent with greater lipid storage capacity. Surprisingly, PEA-15−/− mice exhibited improvements in whole body insulin sensitivity, lower hepatic weight and decreased serum triglycerides indicating a protective phenotype. To determine effects on atherosclerosis, PEA-15−/− mice were crossed with the ApoE−/− mice on a high fat diet. Strikingly, these mice were protected from atherosclerosis and had less hepatic lipid accumulation despite increased adiposity. Therefore, we reveal for the first time that PEA-15 plays a novel role in regulating the expansion of adipose tissue. Decreasing PEA-15 expression increases the sequestering of lipids in adipose tissue, protecting other tissues in obesity, thereby improving metabolic health.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2021-03-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
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Article ; Online: PEA-15 (Phosphoprotein Enriched in Astrocytes 15) Is a Protective Mediator in the Vasculature and Is Regulated During Neointimal Hyperplasia.

Greig, Fiona H / Kennedy, Simon / Gibson, George / Ramos, Joe W / Nixon, Graeme F

Journal of the American Heart Association

2017 Volume 6, Issue 9

Abstract: Background: Neointimal hyperplasia following angioplasty occurs via vascular smooth muscle cell proliferation. The mechanisms involved are not fully understood but include mitogen-activated protein kinases ERK1/2 (extracellular signal-regulated kinases ... ...

Abstract	Background: Neointimal hyperplasia following angioplasty occurs via vascular smooth muscle cell proliferation. The mechanisms involved are not fully understood but include mitogen-activated protein kinases ERK1/2 (extracellular signal-regulated kinases 1 and 2). We recently identified the intracellular mediator PEA-15 (phosphoprotein enriched in astrocytes 15) in vascular smooth muscle cells as a regulator of ERK1/2-dependent proliferation in vitro. PEA-15 acts as a cytoplasmic anchor for ERK1/2, preventing nuclear localization and thereby reducing ERK1/2-dependent gene expression. The aim of the current study was to examine the role of PEA-15 in neointimal hyperplasia in vivo. Method and results: Mice deficient in PEA-15 or wild-type mice were subjected to wire injury of the carotid artery. In uninjured arteries from PEA-15-deficient mice, ERK1/2 had increased nuclear translocation and increased basal ERK1/2-dependent transcription. Following wire injury, arteries from PEA-15-deficient mice developed neointimal hyperplasia at an increased rate compared with wild-type mice. This occurred in parallel with an increase in a proliferative marker and vascular smooth muscle cell proliferation. In wild-type mice, PEA-15 expression was decreased in vascular smooth muscle cells at an early stage before any increase in intima:media ratio. This regulation of PEA-15 expression following injury was also observed in an ex vivo human model of hyperplasia. Conclusions: These results indicate, for the first time, a novel protective role for PEA-15 against inappropriate vascular proliferation. PEA-15 expression may also be repressed during vascular injury, suggesting that maintenance of PEA-15 expression is a novel therapeutic target in vascular disease.
MeSH term(s)	Animals ; Apoptosis Regulatory Proteins ; Carotid Arteries/metabolism ; Carotid Arteries/pathology ; Carotid Artery Injuries/genetics ; Carotid Artery Injuries/metabolism ; Carotid Artery Injuries/pathology ; Carotid Artery Injuries/prevention & control ; Cell Proliferation ; Cells, Cultured ; Disease Models, Animal ; Genetic Predisposition to Disease ; Humans ; Hyperplasia ; Intracellular Signaling Peptides and Proteins/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3/metabolism ; Muscle, Smooth, Vascular/metabolism ; Muscle, Smooth, Vascular/pathology ; Myocytes, Smooth Muscle/metabolism ; Myocytes, Smooth Muscle/pathology ; Neointima ; Phenotype ; Phosphoproteins/deficiency ; Phosphoproteins/genetics ; Phosphoproteins/metabolism ; Phosphorylation ; Saphenous Vein/metabolism ; Saphenous Vein/pathology ; Signal Transduction ; Time Factors ; Tissue Culture Techniques
Chemical Substances	Apoptosis Regulatory Proteins ; Intracellular Signaling Peptides and Proteins ; PEA15 protein, human ; Pea15 protein, mouse ; Phosphoproteins ; Mapk1 protein, mouse (EC 2.7.11.24) ; Mitogen-Activated Protein Kinase 1 (EC 2.7.11.24) ; Mitogen-Activated Protein Kinase 3 (EC 2.7.11.24)
Language	English
Publishing date	2017-09-11
Publishing country	England
Document type	Journal Article
ZDB-ID	2653953-6
ISSN	2047-9980 ; 2047-9980
ISSN (online)	2047-9980
ISSN	2047-9980
DOI	10.1161/JAHA.117.006936
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Article ; Online: Sphingosylphosphorylcholine inhibits macrophage adhesion to vascular smooth muscle cells.

Wirrig, Christiane / McKean, Jenny S / Wilson, Heather M / Nixon, Graeme F

Biochemical pharmacology

2016 Volume 115, Page(s) 43–50

Abstract: Inflammation in de-endothelialised arteries contributes to the development of cardiovascular diseases. The process that initiates this inflammatory response is the adhesion of monocytes/macrophages to exposed vascular smooth muscle cells, typically ... ...

Abstract	Inflammation in de-endothelialised arteries contributes to the development of cardiovascular diseases. The process that initiates this inflammatory response is the adhesion of monocytes/macrophages to exposed vascular smooth muscle cells, typically stimulated by cytokines such as tumour necrosis factor-α (TNF). The aim of this study was to determine the effect of the sphingolipid sphingosylphosphorylcholine (SPC) on the interaction of monocytes/macrophages with vascular smooth muscle cells. Rat aortic smooth muscle cells and rat bone marrow-derived macrophages were co-cultured using an in vitro assay following incubation with sphingolipids to assess inter-cellular adhesion. We reveal that SPC inhibits the TNF-induced adhesion of macrophages to smooth muscle cells. This anti-adhesive effect was the result of SPC-induced changes to the smooth muscle cells (but not the macrophages) and was mediated, at least partly, via the sphingosine 1-phosphate receptor subtype 2. Lipid raft domains were also required. Although SPC did not alter expression or membrane distribution of the adhesion proteins intercellular adhesion molecule-1 and vascular cellular adhesion protein-1 in smooth muscle cells, SPC preincubation inhibited the TNF-induced increase in inducible nitric oxide synthase (NOS2) resulting in a subsequent decrease in nitric oxide production. Inhibiting NOS2 activation in smooth muscle cells led to a decrease in the adhesion of macrophages to smooth muscle cells. This study has therefore delineated a novel pathway which can inhibit the interaction between macrophages and vascular smooth muscle cells via SPC-induced repression of NOS2 expression. This mechanism could represent a potential drug target in vascular disease.
MeSH term(s)	Animals ; Cell Adhesion/drug effects ; Cells, Cultured ; Coculture Techniques ; Macrophages/drug effects ; Male ; Membrane Microdomains/drug effects ; Muscle, Smooth, Vascular/drug effects ; Phosphorylcholine/analogs & derivatives ; Phosphorylcholine/pharmacology ; Rats ; Rats, Sprague-Dawley ; Sphingosine/analogs & derivatives ; Sphingosine/pharmacology ; Tumor Necrosis Factor-alpha/pharmacology
Chemical Substances	Tumor Necrosis Factor-alpha ; sphingosine phosphorylcholine (10216-23-6) ; Phosphorylcholine (107-73-3) ; Sphingosine (NGZ37HRE42)
Language	English
Publishing date	2016-07-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	208787-x
ISSN	1873-2968 ; 0006-2952
ISSN (online)	1873-2968
ISSN	0006-2952
DOI	10.1016/j.bcp.2016.07.004
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Article: Sphingolipids differentially regulate mitogen-activated protein kinases and intracellular Ca2+ in vascular smooth muscle: effects on CREB activation.

Mathieson, Fiona A / Nixon, Graeme F

British journal of pharmacology

2006 Volume 147, Issue 4, Page(s) 351–359

Abstract: 1. Related sphingolipids, sphingosine 1-phosphate (S1P) and sphingosylphosphorylcholine (SPC), have important effects on vascular smooth muscle. The aim of this study was to investigate the intracellular pathways regulated by S1P and SPC in rat cerebral ... ...

Abstract	1. Related sphingolipids, sphingosine 1-phosphate (S1P) and sphingosylphosphorylcholine (SPC), have important effects on vascular smooth muscle. The aim of this study was to investigate the intracellular pathways regulated by S1P and SPC in rat cerebral artery. 2. In cerebral arteries, S1P increased extracellular signal-regulated kinase (ERK)1/2 phosphorylation (5.2+/-1.4-fold increase) but did not activate p38 mitogen-activated protein kinase (p38MAPK) as assessed by immunoblotting. In contrast, SPC increased p38MAPK phosphorylation (3.0+/-0.3-fold increase) but did not stimulate ERK1/2. This differential activation was confirmed by measuring activation of heat shock protein (HSP) 27, a known downstream target of p38MAPK. Only SPC, but not S1P, activated HSP27. 3. In enzymatically dispersed cerebral artery myocytes, SPC increased [Ca2+]i in a concentration-dependent manner (peak response at 10 microM: 0.4+/-0.02 ratio units) as determined using the Ca2+ indicator, Fura 2. In contrast to S1P, the SPC-induced [Ca2+]i increase did not involve intracellular release but was due to Ca2+ influx via L-type Ca2+ channels. 4. Despite differences in signalling, both S1P and SPC phosphorylated the transcription factor cAMP response element-binding protein (CREB). S1P-induced CREB activation was dependent on ERK1/2 and Ca2+-calmodulin-dependent protein kinase (CaMK) activation. CREB activation by SPC required both p38MAPK and CaMK activation, but not ERK1/2. 5. In conclusion, S1P and SPC activate distinct MAP kinase isoforms and increase [Ca2+]i via different mechanisms in rat cerebral artery. This does not affect the ability of S1P or SPC to activate CREB, although this occurs via different pathways.
MeSH term(s)	Animals ; Calcium/metabolism ; Cells, Cultured ; Cerebral Arteries/cytology ; Cerebral Arteries/enzymology ; Cerebral Arteries/metabolism ; Cyclic AMP Response Element-Binding Protein/metabolism ; Enzyme Activation/drug effects ; Lysophospholipids/pharmacology ; Male ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3/metabolism ; Mitogen-Activated Protein Kinases/metabolism ; Muscle, Smooth, Vascular/cytology ; Muscle, Smooth, Vascular/drug effects ; Muscle, Smooth, Vascular/enzymology ; Phosphorylcholine/analogs & derivatives ; Phosphorylcholine/pharmacology ; Rats ; Rats, Sprague-Dawley ; Sphingolipids/pharmacology ; Sphingosine/analogs & derivatives ; Sphingosine/pharmacology
Chemical Substances	Cyclic AMP Response Element-Binding Protein ; Lysophospholipids ; Sphingolipids ; sphingosine phosphorylcholine (10216-23-6) ; Phosphorylcholine (107-73-3) ; sphingosine 1-phosphate (26993-30-6) ; Mitogen-Activated Protein Kinase 1 (EC 2.7.11.24) ; Mitogen-Activated Protein Kinase 3 (EC 2.7.11.24) ; Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; Sphingosine (NGZ37HRE42) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2006-02
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80081-8
ISSN	1476-5381 ; 0007-1188
ISSN (online)	1476-5381
ISSN	0007-1188
DOI	10.1038/sj.bjp.0706600
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Article: Spatial compartmentalization of tumor necrosis factor (TNF) receptor 1-dependent signaling pathways in human airway smooth muscle cells. Lipid rafts are essential for TNF-alpha-mediated activation of RhoA but dispensable for the activation of the NF-kappaB and MAPK pathways.

Hunter, Irene / Nixon, Graeme F

The Journal of biological chemistry

2006 Volume 281, Issue 45, Page(s) 34705–34715

Abstract: Tumor necrosis factor (TNF)-alpha-induced activation of RhoA, mediated by TNF receptor 1 (TNFR1), is a prerequisite step in a pathway that leads to increased 20-kDa light chain of myosin (MLC20) phosphorylation and airway smooth muscle contraction. In ... ...

Abstract	Tumor necrosis factor (TNF)-alpha-induced activation of RhoA, mediated by TNF receptor 1 (TNFR1), is a prerequisite step in a pathway that leads to increased 20-kDa light chain of myosin (MLC20) phosphorylation and airway smooth muscle contraction. In this study, we have investigated the proximal events in TNF-alpha-induced RhoA activation. TNFR1 is localized to both lipid raft and nonraft regions of the plasma membrane in primary human airway smooth muscle cells. TNF-alpha engagement of TNFR1 recruited the adaptor proteins TRADD, TRAF-2, and RIP into lipid rafts and activated RhoA, NF-kappaB, and MAPK pathways. Depletion of cholesterol from rafts with methyl-beta-cyclodextrin caused a redistribution of TNFR1 to nonraft plasma membrane and prevented ligand-induced RhoA activation. By contrast, TNF-alpha-induced activation of NF-kappaB and MAPKs was unaffected by methyl-beta-cyclodextrin indicating that, in airway smooth muscle cells, activation of these pathways occurred independently of lipid rafts. Targeted knockdown of caveolin-1 completely abrogated TNF-alpha-induced RhoA activation, identifying this raft-resident protein as a positive regulator of the activation process. The signaling adaptors TRADD and RIP were also found to be necessary for ligand-induced RhoA activation. Taken together, our results suggest that in airway smooth muscle cells, spatial compartmentalization of TNFR1 provides a mechanism for generating distinct signaling outcomes in response to ligand engagement and define a mechanistic role for lipid rafts and caveolin-1 in TNF-alpha-induced activation of RhoA.
MeSH term(s)	Bronchi/metabolism ; Caveolin 1/antagonists & inhibitors ; Caveolin 1/genetics ; Caveolin 1/metabolism ; Cells, Cultured ; Humans ; I-kappa B Kinase/metabolism ; Immunoblotting ; Immunoprecipitation ; Membrane Microdomains/physiology ; Mitogen-Activated Protein Kinases/metabolism ; Myocytes, Smooth Muscle/metabolism ; NF-kappa B/metabolism ; Phosphorylation ; RNA, Small Interfering/pharmacology ; Receptors, Tumor Necrosis Factor, Type I/metabolism ; Rifampin/analogs & derivatives ; Rifampin/metabolism ; Signal Transduction ; TNF Receptor-Associated Death Domain Protein/metabolism ; TNF Receptor-Associated Factor 2/metabolism ; Tumor Necrosis Factor-alpha/pharmacology ; rhoA GTP-Binding Protein/metabolism
Chemical Substances	3-formyl-23-(O-(beta-glucopyranosyl))rifamycin SV ; CAV1 protein, human ; Caveolin 1 ; NF-kappa B ; RNA, Small Interfering ; Receptors, Tumor Necrosis Factor, Type I ; TNF Receptor-Associated Death Domain Protein ; TNF Receptor-Associated Factor 2 ; Tumor Necrosis Factor-alpha ; I-kappa B Kinase (EC 2.7.11.10) ; Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; rhoA GTP-Binding Protein (EC 3.6.5.2) ; Rifampin (VJT6J7R4TR)
Language	English
Publishing date	2006-09-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M605738200
Database	MEDical Literature Analysis and Retrieval System OnLINE

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