Novel Role of Protein Disulfide Isomerase in the Regulation of NADPH Oxidase Activity: Pathophysiological Implications in Vascular Diseases

2008 ◽  
Vol 10 (6) ◽  
pp. 1101-1114 ◽  
Author(s):  
Francisco R.M. Laurindo ◽  
Denise C. Fernandes ◽  
Angélica M. Amanso ◽  
Lucia R. Lopes ◽  
Célio X.C. Santos
Keyword(s):  
Nadph Oxidase ◽  
Oxidase Activity ◽  
Protein Disulfide Isomerase ◽  
Vascular Diseases ◽  
Disulfide Isomerase ◽  
Nadph Oxidase Activity ◽  
Protein Disulfide

Abstract 776: Protein Disulfide Isomerase Is Involved In Redox Regulation Of Nitric Oxide Output During Laminar Shear Stress In Endothelial Cells

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Denise C Fernandes ◽  
Celio X Santos ◽  
Hanjoong Jo ◽  
Francisco R Laurindo
Keyword(s):  
Endothelial Cells ◽  
Nadph Oxidase ◽  
Oxidase Activity ◽  
Membrane Fraction ◽  
Protein Disulfide Isomerase ◽  
Disulfide Isomerase ◽  
Nadph Oxidase Activity ◽  
Caveolin 1 ◽  
Protein Disulfide ◽  
Laminar Shear

While anti-atherogenic effects of sustained laminar shear (LS) involve NO release from eNOS, increases in LS trigger transient superoxide production via NADPH oxidase. Recently, we showed that NADPH oxidase undergoes thiol-dependent regulation by the thioredoxin superfamily chaperone Protein Disulfide Isomerase (PDI). PDI is known to promote NO internalization via trans-nitrosation reactions. We hypothesized that PDI-dependent support of NADPH oxidase activity affects NO output during sustained LS. Cultured rabbit aortic endothelial cells (RAEC) submitted to LS (15 dynes/cm 2 ) in a cone-plate system for 18h exhibited (vs. static controls): Decreased (~50%) superoxide production (HPLC analysis of DHE oxidation); Decreased (~20%) NADPH-triggered hydrogen peroxide production in membrane fraction (Amplex Red assay); Decreased mRNA expression of Nox1 (67%) and Nox4 (45%) (real-time QPCR); Increased eNOS expression (~50%, western blot) and nitrite levels in culture medium (Δ = 7.1±2.5[SD] μM, NO Analyzer and Griess reaction); Decrease in total and membrane fraction PDI protein expression (~20%) without changes in membrane fraction/total ratio of PDI. RAEC were transfected with c-myc -tagged plasmid coding for wild-type (WT) PDI or PDI mutated in 4 thioredoxin-motif cysteine residues. Forced expression (2-fold) of mutated but not WT PDI led to increase in nitrite output after LS (18h) (Δmutated = 17.2±3.3 μM vs. ΔWT = 7.0±1.9 μM, n=3, p<0.02). Confocal microscopy indicated similar subcellular localization between WT and mutated PDI. PDI co-imunoprecipitated with p22phox NADPH oxidase subunit, but not with eNOS or caveolin-1, either in static condition or after LS. Fractionation studies in sucrose gradients showed that PDI is distributed throughout several fractions in static conditions, including caveolin-1-enriched fractions, but migrates to higher-density fractions, not containing caveolin-1, during sustained LS. These results suggest that PDI is involved in regulation of NO output during LS via its effects on NADPH oxidase activity.

Protein disulfide isomerase is a central regulator of NADPH oxidase activity

2006 ◽  
Vol 45 (3) ◽  
pp. e71
Author(s):  
Mariano Janiszewski ◽  
Katrin Schröder ◽  
Rudi Busse ◽  
Francisco Laurindo ◽  
Ralf P. Brandes
Keyword(s):  
Nadph Oxidase ◽  
Oxidase Activity ◽  
Protein Disulfide Isomerase ◽  
Disulfide Isomerase ◽  
Nadph Oxidase Activity ◽  
Protein Disulfide

scholarly journals Protein disulfide isomerase is a central regulator of NADPH oxidase activity

2006 ◽  
Vol 20 (4) ◽  
Author(s):  
Ralf P. Brandes ◽  
Rudi Busse ◽  
Francisco R Laurindo ◽  
Mariano Janiszewski
Keyword(s):  
Nadph Oxidase ◽  
Oxidase Activity ◽  
Protein Disulfide Isomerase ◽  
Disulfide Isomerase ◽  
Nadph Oxidase Activity ◽  
Protein Disulfide

Protein Disulfide Isomerase (PDI) Regulation of NADPH Oxidase Activity: Effects on Angiotensin II Redox Signaling in Hypertension

2010 ◽  
Vol 49 ◽  
pp. S16
Author(s):  
Livia de Lucca Camargo ◽  
Aline Cristianne Depoli Androwiki ◽  
Graziela Scalianti Ceravolo ◽  
Alexandre Denadai-Souza ◽  
Marcelo Nicolas Muscara ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Nadph Oxidase ◽  
Oxidase Activity ◽  
Protein Disulfide Isomerase ◽  
Redox Signaling ◽  
Disulfide Isomerase ◽  
Nadph Oxidase Activity ◽  
Protein Disulfide

Protein disulfide isomerase (PDI) associates with NADPH oxidase and is required for phagocytosis ofLeishmania chagasipromastigotes by macrophages

2009 ◽  
Vol 86 (4) ◽  
pp. 989-998 ◽  
Author(s):  
Célio X. C. Santos ◽  
Beatriz S. Stolf ◽  
Paulo V. A. Takemoto ◽  
Angélica M. Amanso ◽  
Lucia R. Lopes ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Protein Disulfide Isomerase ◽  
Disulfide Isomerase ◽  
Protein Disulfide

scholarly journals IGF-I increases the expression of fibronectin by Nox4-dependent Akt phosphorylation in renal tubular epithelial cells

2012 ◽  
Vol 302 (1) ◽  
pp. C122-C130 ◽  
Author(s):  
David D. New ◽  
Karen Block ◽  
Basant Bhandhari ◽  
Yves Gorin ◽  
Hanna E. Abboud
Keyword(s):  
Epithelial Cells ◽  
Nadph Oxidase ◽  
Oxidase Activity ◽  
Dominant Negative ◽  
Tubular Epithelial Cells ◽  
Nadph Oxidase Activity ◽  
Akt Phosphorylation ◽  
Fibronectin Expression ◽  
Igf I

Extracellular matrix accumulation contributes to the progression of chronic kidney disease. Many growth factors including insulin-like growth factor-I (IGF-I) enhance matrix protein accumulation. Proximal tubular epithelial cells (PTCs) synthesize matrix proteins. NADPH oxidases are major sources of reactive oxygen species (ROS), important signaling molecules that mediate biological responses in a variety of cells and tissue. We investigated the mechanism by which IGF-I regulates fibronectin accumulation in PTCs and the role of a potential redox-dependent signaling pathway. IGF-I induces an increase in NADPH-dependent superoxide generation, enhances the release of hydrogen peroxide, and increases the expression of NADPH oxidase 4 (Nox4) in PTCs. IGF-I also stimulates phosphorylation of Akt, and inhibition of Akt or its upstream activator phosphatidylinositol 3-kinase attenuates IGF-I-induced fibronectin accumulation. Expression of dominant negative Akt also inhibits IGF-I-induced expression of fibronectin, indicating a role for this kinase in fibronectin accumulation. Expression of dominant negative adenovirus Nox4 inhibits IGF-I-induced NADPH oxidase activity, Akt phosphorylation, and fibronectin protein expression. Moreover, transfection of small interfering RNA targeting Nox4 decreases Nox4 protein expression and blocks IGF-I-induced Akt phosphorylation and the increase in fibronectin, placing Nox4 and ROS upstream of Akt signaling pathway. To confirm the role of Nox4, PTCs were infected with adenovirus construct expressing wild-type Nox4. Ad-Nox4, but not control Ad-green fluorescent protein, upregulated Nox4 expression and increased NADPH oxidase activity as well as fibronectin expression. Taken together, these results provide the first evidence for a role of Nox4 in IGF-I-induced Akt phosphorylation and fibronectin expression in tubular epithelial cells.

scholarly journals The anterior gradient-2 interactome

2020 ◽  
Vol 318 (1) ◽  
pp. C40-C47 ◽  
Author(s):  
Frederic Delom ◽  
M. Aiman Mohtar ◽  
Ted Hupp ◽  
Delphine Fessart
Keyword(s):  
Disulfide Bonds ◽  
Protein Disulfide Isomerase ◽  
Protein Quality ◽  
Physiological Role ◽  
Disulfide Isomerase ◽  
Cellular Effects ◽  
Binding Partners ◽  
Protein Disulfide ◽  
Biological Outcomes

The anterior gradient-2 (AGR2) is an endoplasmic reticulum (ER)-resident protein belonging to the protein disulfide isomerase family that mediates the formation of disulfide bonds and assists the protein quality control in the ER. In addition to its role in proteostasis, extracellular AGR2 is responsible for various cellular effects in many types of cancer, including cell proliferation, survival, and metastasis. Various OMICs approaches have been used to identify AGR2 binding partners and to investigate the functions of AGR2 in the ER and outside the cell. Emerging data showed that AGR2 exists not only as monomer, but it can also form homodimeric structure and thus interact with different partners, yielding different biological outcomes. In this review, we summarize the AGR2 “interactome” and discuss the pathological and physiological role of such AGR2 interactions.

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