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Article ; Online: Communication signals between cardiac fibroblasts and cardiac myocytes.

Ottaviano, Filomena G / Yee, Karen O

2011 Volume 57, Issue 5, Page(s) 513–521

Abstract: Interspersed between cardiac myocytes, cardiac fibroblasts serve mainly as a structural support during ventricular wall thickening from embryogenesis until adulthood. Cardiac fibroblasts, however, may also serve as a source of mitogens, extracellular ... ...

Abstract	Interspersed between cardiac myocytes, cardiac fibroblasts serve mainly as a structural support during ventricular wall thickening from embryogenesis until adulthood. Cardiac fibroblasts, however, may also serve as a source of mitogens, extracellular matrix proteins, cytokines, and growth factors that could affect the phenotype of the cardiac myocyte. The crosstalk between cardiac fibroblasts and myocytes is important during cardiac development and remodeling in response to injury. The cell-to-cell communication involves paracrine signals (cytokines and growth factors), direct interactions (connexins and cadherins) as well as indirect interactions (integrin signaling through the extracellular matrix). In this review, known cardiac fibroblast-cardiac myocyte signaling pathways are briefly examined and their effect on the heart during disease progression is discussed. Furthermore, speculations are made regarding the possibility that vascular endothelial growth factor B can serve as an important signaling molecule between cardiac fibroblasts and cardiac myocytes and could promote cardiac function in compromised hearts.
MeSH term(s)	Animals ; Cell Communication/physiology ; Cytokines/metabolism ; Fibroblasts/immunology ; Fibroblasts/metabolism ; Fibroblasts/physiology ; Heart/physiology ; Humans ; Intercellular Signaling Peptides and Proteins/metabolism ; Myocytes, Cardiac/immunology ; Myocytes, Cardiac/metabolism ; Myocytes, Cardiac/physiology ; Paracrine Communication/physiology
Chemical Substances	Cytokines ; Intercellular Signaling Peptides and Proteins
Language	English
Publishing date	2011-05
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	391970-5
ISSN	1533-4023 ; 0160-2446
ISSN (online)	1533-4023
ISSN	0160-2446
DOI	10.1097/FJC.0b013e31821209ee
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Article: Redox regulation in the extracellular environment.

Ottaviano, Filomena G / Handy, Diane E / Loscalzo, Joseph

Circulation journal : official journal of the Japanese Circulation Society

2007 Volume 72, Issue 1, Page(s) 1–16

Abstract: The oxidizing nature of the extracellular environment is vastly different from the highly reducing nature of the intracellular compartment. The redox potential of the cytosolic compartment of the intracellular environment limits disulfide bond formation, ...

Abstract	The oxidizing nature of the extracellular environment is vastly different from the highly reducing nature of the intracellular compartment. The redox potential of the cytosolic compartment of the intracellular environment limits disulfide bond formation, whereas the oxidizing extracellular environment contains proteins rich in disulfide bonds. If not for an extracellular antioxidant system to eliminate reactive oxygen and nitrogen species, lipid peroxidation and protein oxidation would become excessive, resulting in cellular damage. Many reviews have focused on the role of intracellular antioxidants in the elimination of oxidative stress, but this one will focus on the coordinated action of both intracellular and extracellular antioxidants in limiting cellular oxidant stress.
MeSH term(s)	Antioxidants/metabolism ; Extracellular Fluid/chemistry ; Extracellular Fluid/enzymology ; Extracellular Fluid/metabolism ; Extracellular Space/metabolism ; Oxidants/metabolism ; Oxidation-Reduction ; Reactive Oxygen Species/metabolism
Chemical Substances	Antioxidants ; Oxidants ; Reactive Oxygen Species
Keywords	covid19
Language	English
Publishing date	2007-10-19
Publishing country	Japan
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2068090-9
ISSN	1347-4820 ; 1346-9843
ISSN (online)	1347-4820
ISSN	1346-9843
DOI	10.1253/circj.72.1
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Article ; Online: Regulation of the extracellular antioxidant selenoprotein plasma glutathione peroxidase (GPx-3) in mammalian cells.

Ottaviano, Filomena G / Tang, Shiow-Shih / Handy, Diane E / Loscalzo, Joseph

Molecular and cellular biochemistry

2009 Volume 327, Issue 1-2, Page(s) 111–126

Abstract: Plasma glutathione peroxidase (GPx-3) is a selenocysteine-containing extracellular antioxidant protein that catalyzes the reduction of hydrogen peroxide and lipid hydroperoxides. Selenoprotein expression involves the alternate recognition of a UGA codon ... ...

Abstract	Plasma glutathione peroxidase (GPx-3) is a selenocysteine-containing extracellular antioxidant protein that catalyzes the reduction of hydrogen peroxide and lipid hydroperoxides. Selenoprotein expression involves the alternate recognition of a UGA codon as a selenocysteine codon and requires signals in the 3'-untranslated region (UTR), including a selenocysteine insertion sequence (SECIS), as well as specific translational cofactors. To ascertain regulatory determinants of GPx-3 expression and function, we generated recombinant GPx-3 (rGPX-3) constructs with various 3'-UTR, as well as a Sec73Cys mutant. In transfected Cos7 cells, the Sec73Cys mutant was expressed at higher levels than the wild type rGPx-3, although the wild type rGPx-3 had higher specific activity, similar to plasma purified GPx-3. A 3'-UTR with only the SECIS was insufficient for wild type rGPx-3 protein expression. Selenocompound supplementation and co-transfection with SECIS binding protein 2 increased wild type rGPx-3 expression. These results demonstrate the importance of translational mechanisms in GPx-3 expression.
MeSH term(s)	3' Untranslated Regions/metabolism ; Animals ; Antioxidants/metabolism ; COS Cells ; Cells, Cultured ; Chlorocebus aethiops ; Glutathione Peroxidase/blood ; Glutathione Peroxidase/genetics ; Glutathione Peroxidase/metabolism ; Humans ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Selenium/pharmacology ; Selenoproteins/blood ; Selenoproteins/genetics ; Selenoproteins/metabolism ; Transfection
Chemical Substances	3' Untranslated Regions ; Antioxidants ; Recombinant Proteins ; Selenoproteins ; GPX3 protein, human (EC 1.11.1.-) ; Glutathione Peroxidase (EC 1.11.1.9) ; Selenium (H6241UJ22B)
Language	English
Publishing date	2009-02-15
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	184833-1
ISSN	1573-4919 ; 0300-8177
ISSN (online)	1573-4919
ISSN	0300-8177
DOI	10.1007/s11010-009-0049-x
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Article: Regulation of the extracellular antioxidant selenoprotein plasma glutathione peroxidase (GPx-3) in mammalian cells

Ottaviano, Filomena G / Tang, Shiow-Shih / Handy, Diane E / Loscalzo, Joseph

Molecular and cellular biochemistry. 2009 July, v. 327, no. 1-2

2009

Abstract	Plasma glutathione peroxidase (GPx-3) is a selenocysteine-containing extracellular antioxidant protein that catalyzes the reduction of hydrogen peroxide and lipid hydroperoxides. Selenoprotein expression involves the alternate recognition of a UGA codon as a selenocysteine codon and requires signals in the 3'-untranslated region (UTR), including a selenocysteine insertion sequence (SECIS), as well as specific translational cofactors. To ascertain regulatory determinants of GPx-3 expression and function, we generated recombinant GPx-3 (rGPX-3) constructs with various 3'-UTR, as well as a Sec73Cys mutant. In transfected Cos7 cells, the Sec73Cys mutant was expressed at higher levels than the wild type rGPx-3, although the wild type rGPx-3 had higher specific activity, similar to plasma purified GPx-3. A 3'-UTR with only the SECIS was insufficient for wild type rGPx-3 protein expression. Selenocompound supplementation and co-transfection with SECIS binding protein 2 increased wild type rGPx-3 expression. These results demonstrate the importance of translational mechanisms in GPx-3 expression.
Language	English
Dates of publication	2009-07
Size	p. 111-126.
Publisher	Springer US
Publishing place	Boston
Document type	Article
ZDB-ID	184833-1
ISSN	1573-4919 ; 0300-8177
ISSN (online)	1573-4919
ISSN	0300-8177
DOI	10.1007/s11010-009-0049-x
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Article ; Online: Pathological role of serum- and glucocorticoid-regulated kinase 1 in adverse ventricular remodeling.

Das, Saumya / Aiba, Takeshi / Rosenberg, Michael / Hessler, Katherine / Xiao, Chunyang / Quintero, Pablo A / Ottaviano, Filomena G / Knight, Ashley C / Graham, Evan L / Boström, Pontus / Morissette, Michael R / del Monte, Federica / Begley, Michael J / Cantley, Lewis C / Ellinor, Patrick T / Tomaselli, Gordon F / Rosenzweig, Anthony

Circulation

2012 Volume 126, Issue 18, Page(s) 2208–2219

Abstract: Background: Heart failure is a growing cause of morbidity and mortality. Cardiac phosphatidylinositol 3-kinase signaling promotes cardiomyocyte survival and function, but it is paradoxically activated in heart failure, suggesting that chronic activation ...

Abstract	Background: Heart failure is a growing cause of morbidity and mortality. Cardiac phosphatidylinositol 3-kinase signaling promotes cardiomyocyte survival and function, but it is paradoxically activated in heart failure, suggesting that chronic activation of this pathway may become maladaptive. Here, we investigated the downstream phosphatidylinositol 3-kinase effector, serum- and glucocorticoid-regulated kinase-1 (SGK1), in heart failure and its complications. Methods and results: We found that cardiac SGK1 is activated in human and murine heart failure. We investigated the role of SGK1 in the heart by using cardiac-specific expression of constitutively active or dominant-negative SGK1. Cardiac-specific activation of SGK1 in mice increased mortality, cardiac dysfunction, and ventricular arrhythmias. The proarrhythmic effects of SGK1 were linked to biochemical and functional changes in the cardiac sodium channel and could be reversed by treatment with ranolazine, a blocker of the late sodium current. Conversely, cardiac-specific inhibition of SGK1 protected mice after hemodynamic stress from fibrosis, heart failure, and sodium channel alterations. Conclusions: SGK1 appears both necessary and sufficient for key features of adverse ventricular remodeling and may provide a novel therapeutic target in cardiac disease.
MeSH term(s)	Acetanilides/therapeutic use ; Animals ; Cardiomegaly, Exercise-Induced ; Cardiomyopathy, Dilated/enzymology ; Consensus Sequence ; Disease Models, Animal ; Electrocardiography ; Enzyme Induction ; Heart Failure/enzymology ; Humans ; Hypertension/complications ; Immediate-Early Proteins/chemistry ; Immediate-Early Proteins/deficiency ; Immediate-Early Proteins/genetics ; Immediate-Early Proteins/metabolism ; Immediate-Early Proteins/physiology ; Ion Channel Gating/drug effects ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; NAV1.5 Voltage-Gated Sodium Channel/chemistry ; NAV1.5 Voltage-Gated Sodium Channel/drug effects ; NAV1.5 Voltage-Gated Sodium Channel/physiology ; Phosphatidylinositol 3-Kinases/physiology ; Phosphorylation ; Piperazines/therapeutic use ; Protein Interaction Mapping ; Protein Processing, Post-Translational ; Protein-Serine-Threonine Kinases/chemistry ; Protein-Serine-Threonine Kinases/deficiency ; Protein-Serine-Threonine Kinases/genetics ; Protein-Serine-Threonine Kinases/metabolism ; Protein-Serine-Threonine Kinases/physiology ; Ranolazine ; Sodium Channel Blockers/pharmacology ; Sodium Channel Blockers/therapeutic use ; Tachycardia, Ventricular/enzymology ; Tachycardia, Ventricular/etiology ; Ventricular Remodeling/physiology
Chemical Substances	Acetanilides ; Immediate-Early Proteins ; NAV1.5 Voltage-Gated Sodium Channel ; Piperazines ; Scn5a protein, mouse ; Sodium Channel Blockers ; Ranolazine (A6IEZ5M406) ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; serum-glucocorticoid regulated kinase (EC 2.7.11.1)
Language	English
Publishing date	2012-09-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80099-5
ISSN	1524-4539 ; 0009-7322 ; 0069-4193 ; 0065-8499
ISSN (online)	1524-4539
ISSN	0009-7322 ; 0069-4193 ; 0065-8499
DOI	10.1161/CIRCULATIONAHA.112.115592
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Article ; Online: Tumor-to-tumor metastasis: breast cancer metastatic to thymic epithelial tumor.

Moretto, Roberto / Cella, Chiara A / Raimondo, Lucia / Formisano, Luigi / Nappi, Lucia / Rescigno, Pasquale / Buonerba, Carlo / Calabrese, Filomena / Ottaviano, Margaret / Di Lorenzo, Giuseppe / Matano, Elide / Damiano, Vincenzo / Palmieri, Giovannella

Anti-cancer drugs

2013 Volume 24, Issue 7, Page(s) 759–764

Abstract: Tumor-to-tumor metastasis is a rare phenomenon, with around 150 cases being reported in the literature. Breast cancer is the second most commonly reported donor tumor after lung cancer, but thymic epithelial tumors have never been reported as recipient ... ...

Abstract	Tumor-to-tumor metastasis is a rare phenomenon, with around 150 cases being reported in the literature. Breast cancer is the second most commonly reported donor tumor after lung cancer, but thymic epithelial tumors have never been reported as recipient tumors. Furthermore, the thymus is rarely affected by metastases. To our knowledge, the present report is the first case of breast cancer metastatic to thymic epithelial tumor.
MeSH term(s)	Adult ; Breast Neoplasms/diagnosis ; Breast Neoplasms/drug therapy ; Female ; Humans ; Neoplasms, Glandular and Epithelial/diagnosis ; Neoplasms, Glandular and Epithelial/drug therapy ; Neoplasms, Glandular and Epithelial/secondary ; Thymus Neoplasms/diagnosis ; Thymus Neoplasms/drug therapy ; Thymus Neoplasms/secondary
Language	English
Publishing date	2013-08
Publishing country	England
Document type	Case Reports ; Journal Article
ZDB-ID	1065301-6
ISSN	1473-5741 ; 0959-4973
ISSN (online)	1473-5741
ISSN	0959-4973
DOI	10.1097/CAD.0b013e328362a68b
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Article ; Online: Capecitabine plus gemcitabine in thymic epithelial tumors: final analysis of a Phase II trial.

Palmieri, Giovannella / Buonerba, Carlo / Ottaviano, Margaret / Federico, Piera / Calabrese, Filomena / Von Arx, Claudia / De Maio, Ana Paula / Marino, Mirella / Lalle, Maurizio / Montella, Liliana / Merola, Carmela / Milella, Michele / Bergaglio, Marina / Di Lorenzo, Giuseppe / Damiano, Vincenzo

Future oncology (London, England)

2014 Volume 10, Issue 14, Page(s) 2141–2147

Abstract: Background: A multi-institutional Phase II trial was initiated in 2005 to test the combination gemcitabine and capecitabine in patients with thymic epithelial malignancies (TETs).: Patients & methods: Patients with histologic confirmation of TET ... ...

Abstract	Background: A multi-institutional Phase II trial was initiated in 2005 to test the combination gemcitabine and capecitabine in patients with thymic epithelial malignancies (TETs). Patients & methods: Patients with histologic confirmation of TET diagnosis by central review who had received >1 systemic chemotherapy treatment were included. Patients received oral capecitabine (650 mg/mq twice daily on days 1-14) and intravenous gemcitabine (1000 mg/mq on days 1 and 8 every 3 weeks). Results: Of the 30 patients included (18 men, 12 women; median age: 57 years, range: 48-61 years), the majority (73%) had thymoma, and the remaining thymic carcinoma. Eight patients developed grade 3-4 neutropenia. A total of 12 patients had a response. Median progression-free survival was 11 months (range: 6.5-16.5). Conclusion: Capecitabine and gemcitabine is highly active in TETs.
MeSH term(s)	Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Capecitabine ; Deoxycytidine/administration & dosage ; Deoxycytidine/analogs & derivatives ; Female ; Fluorouracil/administration & dosage ; Fluorouracil/analogs & derivatives ; Humans ; Male ; Middle Aged ; Neoplasm Metastasis ; Neoplasm Staging ; Neoplasms, Glandular and Epithelial/diagnosis ; Neoplasms, Glandular and Epithelial/drug therapy ; Neoplasms, Glandular and Epithelial/mortality ; Positron-Emission Tomography ; Retreatment ; Thymus Neoplasms/diagnosis ; Thymus Neoplasms/drug therapy ; Thymus Neoplasms/mortality ; Tomography, X-Ray Computed ; Treatment Outcome
Chemical Substances	Deoxycytidine (0W860991D6) ; Capecitabine (6804DJ8Z9U) ; gemcitabine (B76N6SBZ8R) ; Fluorouracil (U3P01618RT)
Language	English
Publishing date	2014-11
Publishing country	England
Document type	Clinical Trial, Phase II ; Journal Article ; Multicenter Study
ZDB-ID	2184533-5
ISSN	1744-8301 ; 1479-6694
ISSN (online)	1744-8301
ISSN	1479-6694
DOI	10.2217/fon.14.144
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Article ; Online: A Regional ADHD Center-Based Network Project for the Diagnosis and Treatment of Children and Adolescents With ADHD.

Bonati, Maurizio / Reale, Laura / Zanetti, Michele / Cartabia, Massimo / Fortinguerra, Filomena / Capovilla, Giuseppe / Chiappedi, Matteo / Costantino, Antonella / Effedri, Paola / Luoni, Chiara / Martinelli, Ottaviano / Molteni, Massimo / Ottolini, Alberto / Saccani, Monica

Journal of attention disorders

2015 Volume 22, Issue 12, Page(s) 1173–1184

Abstract: Objective: We aimed to define the sociodemographic, clinical, and prescription profiles of the participants enrolled in the Italian Lombardy ADHD Register.: Method: Data on patients evaluated by the 18 regional ADHD reference centers in the 2012 to ... ...

Abstract	Objective: We aimed to define the sociodemographic, clinical, and prescription profiles of the participants enrolled in the Italian Lombardy ADHD Register. Method: Data on patients evaluated by the 18 regional ADHD reference centers in the 2012 to 2013 period were analyzed. Results: Seven hundred fifty-three of 1,150 (65%) suspected patients received a diagnosis of ADHD. In 24% of cases, there was a family history of ADHD. Four hundred eighty-three (64%) patients had at least one psychopathological disorder, the more common of which were learning disorders (35%). Eighty-four percent of patients received a prescription for psychoeducational interventions, 2% received only pharmacological treatment, and 14% a combination of both. Compared with patients treated with psychoeducational intervention alone, patients with drug prescriptions more commonly presented values of Clinical Global Impressions - Severity scale (CGI-S) of 5 or higher ( p < .0001). Conclusion: A continuous and systematic monitoring of patterns of care is essential in promoting significant improvements in clinical practice and ensuring an efficient and homogeneous quality of care.
MeSH term(s)	Adolescent ; Attention Deficit Disorder with Hyperactivity/diagnosis ; Attention Deficit Disorder with Hyperactivity/epidemiology ; Attention Deficit Disorder with Hyperactivity/therapy ; Child ; Child, Preschool ; Clinical Protocols ; Continuity of Patient Care ; Female ; Humans ; Incidence ; Italy/epidemiology ; Learning Disorders/epidemiology ; Male ; Mental Health Services/statistics & numerical data ; Registries
Language	English
Publishing date	2015-08-28
Publishing country	United States
Document type	Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't
ZDB-ID	2004350-8
ISSN	1557-1246 ; 1087-0547
ISSN (online)	1557-1246
ISSN	1087-0547
DOI	10.1177/1087054715599573
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Article ; Online: Methylation and acetylation of 15-hydroxyanandamide modulate its interaction with the endocannabinoid system.

Amadio, Daniele / Fezza, Filomena / Catanzaro, Giuseppina / Incani, Ottaviano / van Zadelhoff, Guus / Finazzi Agrò, Alessandro / Maccarrone, Mauro

Biochimie

2010 Volume 92, Issue 4, Page(s) 378–387

Abstract: The biological activity of endocannabinoids like anandamide (AEA) and 2-arachidonoylglycerol (2-AG) is subjected in vivo to a "metabolic control", exerted mainly by catabolic enzymes. AEA is inactivated by fatty acid amide hydrolase (FAAH), that is ... ...

Abstract	The biological activity of endocannabinoids like anandamide (AEA) and 2-arachidonoylglycerol (2-AG) is subjected in vivo to a "metabolic control", exerted mainly by catabolic enzymes. AEA is inactivated by fatty acid amide hydrolase (FAAH), that is inhibited competitively by hydroxyanandamides (HAEAs) generated from AEA by lipoxygenase activity. Among these derivatives, 15-HAEA has been shown to be an effective (K(i) approximately 0.6 muM) FAAH inhibitor, that blocks also type-1 cannabinoid receptor (CB1R) but not other components of the "endocannabinoid system (ECS)", like the AEA transporter (AMT) or CB2R. Here, we extended the study of the effect of 15-HAEA on the AEA synthetase (NAPE-PLD) and the AEA-binding vanilloid receptor (TRPV1), showing that 15-HAEA activates the former (up to approximately 140% of controls) and inhibits the latter protein (down to approximately 70%). We also show that 15-HAEA halves the synthesis of 2-AG and almost doubles the transport of this compound across the membrane. In addition, we synthesized methyl and acetyl derivatives of 15-HAEA (15-MeOAEA and 15-AcOAEA, respectively), in order to check their ability to modulate FAAH and the other ECS elements. In fact, methylation and acetylation are common biochemical reactions in the cellular environment. We show that 15-MeOAEA, unlike 15-AcOAEA, is still a powerful competitive inhibitor of FAAH (K(i) approximately 0.7 muM), and that both derivatives have negligible interactions with the other proteins of ECS. Therefore, 15-MeOAEA is a FAAH inhibitor more selective than 15-HAEA. Further molecular dynamics analysis gave clues to the molecular requirements for the interaction of 15-HAEA and 15-MeOAEA with FAAH.
MeSH term(s)	Acetylation ; Amidohydrolases/metabolism ; Animals ; Arachidonic Acids/metabolism ; Arachidonic Acids/pharmacology ; Cannabinoid Receptor Modulators/metabolism ; Endocannabinoids ; Kinetics ; Methylation ; Mice ; Phospholipase D/drug effects ; Phospholipase D/metabolism ; Polyunsaturated Alkamides/metabolism ; Polyunsaturated Alkamides/pharmacology ; Receptor, Cannabinoid, CB1/drug effects ; TRPV Cation Channels/metabolism
Chemical Substances	15-hydroxyanandamide ; Arachidonic Acids ; Cannabinoid Receptor Modulators ; Endocannabinoids ; Polyunsaturated Alkamides ; Receptor, Cannabinoid, CB1 ; TRPV Cation Channels ; TRPV1 protein, mouse ; N-acylphosphatidylethanolamine phospholipase D, mouse (EC 3.1.4.4) ; Phospholipase D (EC 3.1.4.4) ; Amidohydrolases (EC 3.5.-) ; fatty-acid amide hydrolase (EC 3.5.1.-)
Language	English
Publishing date	2010-04
Publishing country	France
Document type	Journal Article
ZDB-ID	120345-9
ISSN	1638-6183 ; 0300-9084
ISSN (online)	1638-6183
ISSN	0300-9084
DOI	10.1016/j.biochi.2010.01.001
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Article ; Online: Promoter polymorphisms in the plasma glutathione peroxidase (GPx-3) gene: a novel risk factor for arterial ischemic stroke among young adults and children.

Voetsch, Barbara / Jin, Richard C / Bierl, Charlene / Benke, Kelly S / Kenet, Gili / Simioni, Paolo / Ottaviano, Filomena / Damasceno, Benito P / Annichino-Bizacchi, Joyce M / Handy, Diane E / Loscalzo, Joseph

Stroke

2007 Volume 38, Issue 1, Page(s) 41–49

Abstract: Background and purpose: Plasma glutathione peroxidase (GPx-3)-deficiency increases extracellular oxidant stress, decreases bioavailable nitric oxide, and promotes platelet activation. The aim of this study is to identify polymorphisms in the GPx-3 gene, ...

Abstract	Background and purpose: Plasma glutathione peroxidase (GPx-3)-deficiency increases extracellular oxidant stress, decreases bioavailable nitric oxide, and promotes platelet activation. The aim of this study is to identify polymorphisms in the GPx-3 gene, examine their relationship to arterial ischemic stroke (AIS) in a large series of children and young adults, and determine their functional molecular consequences. Methods: We studied the GPx-3 gene promoter from 123 young adults with idiopathic AIS and 123 age- and gender-matched controls by single-stranded conformational polymorphism and sequencing analysis. A second, independent population with childhood stroke was used for a replication study. We identified 8 novel, strongly linked polymorphisms in the GPx-3 gene promoter that formed 2 main haplotypes (H1 and H2). The transcriptional activity of the 2 most prevalent haplotypes was studied with luciferase reporter gene constructs. Results: The H2 haplotype was over-represented in both patient populations and associated with an independent increase in the risk of AIS in young adults (odds ratio=2.07, 95% CI=1.03 to 4.47; P=0.034) and children (odds ratio=2.13, 95% CI=1.23 to 4.90; P=0.027). In adults simultaneously exposed to vascular risk factors, the risk of AIS approximately doubled (odds ratio=5.18, 95% CI=1.82 to 15.03; P<0.001). Transcriptional activity of the H2 haplotype was lower than that of the H1 haplotype, especially after upregulation by hypoxia (normalized relative luminescence: 3.54+/-0.32 versus 2.47+/-0.26; P=0.0083). Conclusions: These findings indicate that a novel GPx-3 promoter haplotype is an independent risk factor for AIS in children and young adults. This haplotype reduces the gene's transcriptional activity, thereby compromising gene expression and plasma antioxidant and antithrombotic activities.
MeSH term(s)	Adult ; Antioxidants/metabolism ; Blood Coagulation/genetics ; Brain Ischemia/blood ; Brain Ischemia/enzymology ; Brain Ischemia/genetics ; Child ; DNA Mutational Analysis ; Enzyme Activation/genetics ; Female ; Gene Expression Regulation, Enzymologic/genetics ; Gene Frequency ; Genetic Markers/genetics ; Genetic Predisposition to Disease/genetics ; Genetic Testing ; Glutathione Peroxidase/genetics ; Haplotypes ; Humans ; Hypoxia/genetics ; Hypoxia/metabolism ; Hypoxia/physiopathology ; Male ; Mutation/genetics ; Polymorphism, Genetic/genetics ; Promoter Regions, Genetic/genetics ; Risk Factors ; Stroke/blood ; Stroke/enzymology ; Stroke/genetics ; Transcriptional Activation/genetics
Chemical Substances	Antioxidants ; Genetic Markers ; GPX3 protein, human (EC 1.11.1.-) ; Glutathione Peroxidase (EC 1.11.1.9)
Language	English
Publishing date	2007-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80381-9
ISSN	1524-4628 ; 0039-2499 ; 0749-7954
ISSN (online)	1524-4628
ISSN	0039-2499 ; 0749-7954
DOI	10.1161/01.STR.0000252027.53766.2b
Database	MEDical Literature Analysis and Retrieval System OnLINE

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