Nox2 B-loop peptide, Nox2ds, specifically inhibits the NADPH oxidase Nox2

Csányi, Gábor; Cifuentes-Pagano, Eugenia; Ghouleh, Imad Al; Ranayhossaini, Daniel J.; Egaña, Loreto; Lopes, Lucia Rossetti; Jackson, Heather; Kelley, Eric E.; Pagano, Patrick J.

doi:10.1016/j.freeradbiomed.2011.04.025

Cited by 117 publications

(104 citation statements)

References 49 publications

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“…Compressed gases were purchased from Air Products and Chemicals, Inc. (Allentown, PA). NADPH oxidase inhibitory peptide (Nox2ds), which selectively inhibits the interaction between Nox2 and p47 phox , with the sequence NH 3 -CSTRVRRQL-CONH 2 , and Scrmb-Nox2ds, a control scrambled amino acid peptide with sequence NH 3 -CLRVTRQSR-CONH 2 , were purchased from American Peptide Co. (Sunnyvale, CA) (30). N-3-(Aminomethyl) benzyl acetamine (NSC 23766), a Rac inhibitor; 3,4-dihydro-6-[ [4-[[[3-(methylsulfonyl) ϩ ,K ϩ -ATPase (a "flippase"); and quercetin-3-rutinoside, a protein-disulfide isomerase (PDI) inhibitor, were purchased from Tocris Bioscience (Ellisville, MO).…”

Section: Methodsmentioning

confidence: 99%

Neutrophils Generate Microparticles during Exposure to Inert Gases Due to Cytoskeletal Oxidative Stress

Thom

Bhopale

Yang

2014

Journal of Biological Chemistry

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Background: Microparticles are generated in vivo with exposures to high pressure gases by unclear mechanisms. Results: High inert gas pressure causes singlet oxygen formation, which initiates a cycle of actin S-nitrosylation, nitric-oxide synthase-2, and NADPH oxidase activation leading to microparticle formation. Conclusion: Inert gas-mediated oxidative stress causes microparticle production. Significance: This mechanism may initiate events leading to decompression sickness.

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Section: Methodsmentioning

confidence: 99%

Neutrophils Generate Microparticles during Exposure to Inert Gases Due to Cytoskeletal Oxidative Stress

Thom

Bhopale

Yang

2014

Journal of Biological Chemistry

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“…NOX2ds-tat inhibited NOX2 with an IC 50 of 0.74 lM, but did not inhibit NOX1 or NOX4 in cell lines specifically expressing these isoforms (53). NOX2ds-tat also inhibited O 2 -anion production from cultured endothelial cells (169), human resistance artery smooth muscle cells (304), and platelets (147).…”

Section: Fig 2 Structures Of Some Commonly Used Nox Inhibitorsmentioning

confidence: 99%

NOX2 As a Target for Drug Development: Indications, Possible Complications, and Progress

Diebold

Smith

Yang

et al. 2015

Antioxidants & Redox Signaling

106

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Significance: NOX2 is important for host defense, and yet is implicated in a large number of diseases in which inflammation plays a role in pathogenesis. These include acute and chronic lung inflammatory diseases, stroke, traumatic brain injury, and neurodegenerative diseases, including Alzheimer's and Parkinson's Diseases. Recent Advances: Recent drug development programs have targeted several NOX isoforms that are implicated in a variety of diseases. The focus has been primarily on NOX4 and NOX1 rather than on NOX2, due, in part, to concerns about possible immunosuppressive side effects. Nevertheless, NOX2 clearly contributes to the pathogenesis of many inflammatory diseases, and its inhibition is predicted to provide a novel therapeutic approach. Critical Issues: Possible side effects that might arise from targeting NOX2 are discussed, including the possibility that such inhibition will contribute to increased infections and/or autoimmune disorders. The state of the field with regard to existing NOX2 inhibitors and targeted development of novel inhibitors is also summarized. Future Directions: NOX2 inhibitors show particular promise for the treatment of inflammatory diseases, both acute and chronic. Theoretical side effects include pro-inflammatory and autoimmune complications and should be considered in any therapeutic program, but in our opinion, available data do not indicate that they are sufficiently likely to eliminate NOX2 as a drug target, particularly when weighed against the seriousness of many NOX2-related indications. Model studies demonstrating efficacy with minimal side effects are needed to encourage future development of NOX2 inhibitors as therapeutic agents. Antioxid. Redox Signal. 23,

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“…The fluorescence signal from adherent human platelets was ablated by the cell-permeable superoxide scavengers TEMPOL (1 mmol/L) and MnTMPyP (100 mmol/L) ( Figure 2F), suggesting the presence of intracellular ROS. Pretreatment of platelets with the specific NOX2 inhibitor peptide gp91ds-tat, 30 but not its scrambled control sc-gp91ds-tat (both 2 mmol/L), prevented oxLDL stimulation of ROS ( Figure 2F). Activation of gp91 phox /NOX2 represents a major source of intracellular platelet ROS.…”

Section: Org Frommentioning

confidence: 99%

Oxidized LDL activates blood platelets through CD36/NOX2–mediated inhibition of the cGMP/protein kinase G signaling cascade

Magwenzi

Woodward

Wraith

et al. 2015

Blood

142

150

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Key Points• oxLDL binds platelet CD36 to stimulate tyrosine kinaseand PKC-dependent activation of NOX2 and generation of ROS.• oxLDL-and hyperlipidemiainduced ROS mediate platelet desensitization to inhibitory cGMP signaling to facilitate platelet activation and thrombus formation.Oxidized low-density lipoprotein (oxLDL) promotes unregulated platelet activation in dyslipidemic disorders. Although oxLDL stimulates activatory signaling, it is unclear how these events drive accelerated thrombosis. Here, we describe a mechanism for oxLDLmediated platelet hyperactivity that requires generation of reactive oxygen species (ROS). Under arterial flow, oxLDL triggered sustained generation of platelet intracellular ROS, which was blocked by CD36 inhibitors, mimicked by CD36-specific oxidized phospholipids, and ablated in CD36 2/2 murine platelets. oxLDL-induced ROS generation was blocked by the reduced NAD phosphate oxidase 2 (NOX2) inhibitor, gp91ds-tat, and absent in NOX2 2/2 mice. The synthesis of ROS by oxLDL/CD36 required Src-family kinases and protein kinase C (PKC)-dependent phosphorylation and activation of NOX2. In functional assays, oxLDL abolished guanosine 39,59-cyclic monophosphate (cGMP)-mediated signaling and inhibited platelet aggregation and arrest under flow. This was prevented by either pharmacologic inhibition of NOX2 in human platelets or genetic ablation of NOX2 in murine platelets. Platelets from hyperlipidemic mice were also found to have a diminished sensitivity to cGMP when tested ex vivo, a phenotype that was corrected by infusion of gp91ds-tat into the mice. This study demonstrates that oxLDL and hyperlipidemia stimulate the generation of NOX2-derived ROS through a CD36-PKC pathway and may promote platelet hyperactivity through modulation of cGMP signaling. (Blood. 2015;125(17):2693-2703

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Nox2 B-loop peptide, Nox2ds, specifically inhibits the NADPH oxidase Nox2

Cited by 117 publications

References 49 publications

Neutrophils Generate Microparticles during Exposure to Inert Gases Due to Cytoskeletal Oxidative Stress

Neutrophils Generate Microparticles during Exposure to Inert Gases Due to Cytoskeletal Oxidative Stress

NOX2 As a Target for Drug Development: Indications, Possible Complications, and Progress

Oxidized LDL activates blood platelets through CD36/NOX2–mediated inhibition of the cGMP/protein kinase G signaling cascade

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