Mycophenolic Acid Is a New Nox2 Inhibitor

Lassègue, Bernard; Griendling, Kathy K.

doi:10.1161/01.hyp.0000251161.93696.d0

Cited by 7 publications

(3 citation statements)

References 7 publications

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“…In these situations, use of alternative, ROS-independent therapies (e.g. targeted use of cyclosporine or mycophenolate (66–68)) might be preferred.…”

Section: Discussionmentioning

confidence: 99%

Programmed Death-1 Controls T Cell Survival by Regulating Oxidative Metabolism

Tkachev

Goodell

Opipari

et al. 2015

The Journal of Immunology

101

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The co-inhibitory receptor programmed death-1 (PD-1) maintains immune homeostasis by negatively regulating T cell function and survival. Blockade of PD-1 increases the severity of graft-versus-host disease (GVHD), but the interplay between PD-1 inhibition and T cell metabolism is not well studied. We found that both murine and human alloreactive T cells concomitantly up-regulated PD-1 expression and increased levels of reactive oxygen species (ROS) following allogeneic bone marrow transplantation. This PD-1HiROSHi phenotype was specific to alloreactive T cells and was not observed in syngeneic T cells during homeostatic proliferation. Blockade of PD-1 signaling decreased both mitochondrial H2O2 and total cellular ROS levels and PD-1 driven increases in ROS were dependent upon the oxidation of fatty acids, as treatment with etomoxir nullified changes in ROS levels following PD-1 blockade. Downstream of PD-1, elevated ROS levels impaired T cell survival in a process reversed by anti-oxidants. Furthermore, PD-1 driven changes in ROS were fundamental to establishing a cell’s susceptibility to subsequent metabolic inhibition, as blockade of PD-1 decreased the efficacy of later F1F0-ATP synthase modulation. These data indicate that PD-1 facilitates apoptosis in alloreactive T cells by increasing reactive oxygen species in a process dependent upon the oxidation of fat. In addition, blockade of PD-1 undermines the potential for subsequent metabolic inhibition, an important consideration given the increasing use of anti-PD-1 therapies in the clinic.

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“…In these situations, use of alternative, ROS-independent therapies (e.g. targeted use of cyclosporine or mycophenolate (66–68)) might be preferred.…”

Section: Discussionmentioning

confidence: 99%

Programmed Death-1 Controls T Cell Survival by Regulating Oxidative Metabolism

Tkachev

Goodell

Opipari

et al. 2015

The Journal of Immunology

101

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“…Interestingly, application of NOX2-based peptide inhibitor gp91 ds-tat [33] (Fig. 4) or Rac1/NOX2 inhibitor mycophenolic acid [34] (Supplementary Fig. IV) prevented the coronary arteriolar dysfunction mediated by ET-1.…”

Section: Discussionmentioning

confidence: 99%

“…The involvements of superoxide, hydrogen peroxide (H 2 O 2 ) and peroxynitrite in the adverse effect of ET-1 were also examined by co-incubating the vessels with ET-1 plus superoxide scavengers Tempol (1 mmol/L) [28, 29] or MnTBAP (10 μmol/L) [30], H 2 O 2 scavenger catalase (1,000 units/mL) [31], and peroxynitrite scavenger urate (0.1 mmol/L) [29] for 60 minutes, respectively. To determine the contribution of superoxide generation enzyme NADPH oxidase (NOX) in mediating the ET-1 effect, vasodilations to serotonin and adenosine were studied in separate groups of vessels treated with ET-1 (0.1 nmol/L) in combination with NOX inhibitor apocynin (100 μmol/L) [28], VAS2870 (10 μmol/L) [32], NOX2-based assembly inhibitor gp91 ds-tat (10 μmol/L) [33] or Rac1/NOX2 inhibitor mycophenolic acid (10 μmol/L, Santa Cruz Biotechnology) [34]. The role of xanthine oxidase was investigated using its inhibitor allopurinol (10 μmol/L) [35].…”

Section: Methodsmentioning

confidence: 99%

Endothelin-1 impairs coronary arteriolar dilation: Role of p38 kinase-mediated superoxide production from NADPH oxidase

Thengchaisri

Hein

Ren

et al. 2015

Journal of Molecular and Cellular Cardiology

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Elevated levels of endothelin-1 (ET-1), a potent vasoactive peptide, are implicated as a risk factor for cardiovascular diseases by exerting vasoconstriction. The aim of this study was to address whether ET-1, at sub-vasomotor concentrations, elicits adverse effects on coronary microvascular function. Porcine coronary arterioles (50–100 μm) were isolated, cannulated and pressurized without flow for in vitro study. Diameter changes were recorded using a videomicrometer. Arterioles developed basal tone (60±3 μm) and dilated to the endothelium-dependent nitric oxide (NO)-mediated vasodilators serotonin (1 nmol/L to 0.1 μmol/L) and adenosine (1 nmol/L to 10 μmol/L). Treating the vessels with a clinically relevant sub-vasomotor concentration of ET-1 (10 pmol/L, 60 minutes) significantly attenuated arteriolar dilations to adenosine and serotonin but not to endothelium-independent vasodilator sodium nitroprusside. The arteriolar wall contains ETA receptors and the adverse effect of ET-1 was prevented by ETA receptor antagonist BQ123, the superoxide scavenger Tempol, the NADPH oxidase inhibitors apocynin and VAS2870, the NOX2-based NADPH oxidase inhibitor gp91 ds-tat, or the p38 kinase inhibitor SB203580. However, ETB receptor antagonist BQ788, H2O2 scavenger catalase, scrambled gp91 ds-tat, or inhibitors of xanthine oxidase (allopurinol), PKC (Gö 6983), Rho kinase (Y27632), and c-Jun N-terminal kinase (SP600125) did not protect the vessel. Immunohistochemical staining showed that ET-1 elicited Tempol-, apocynin- and SB203580-sensitive superoxide production in the arteriolar wall. Our results indicate that exposure of coronary arterioles to a pathophysiological, sub-vasomotor concentration of ET-1 leads to vascular dysfunction by impairing endothelium-dependent NO-mediated dilation via p38 kinase-mediated production of superoxide from NADPH oxidase following ETA receptor activation.

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Small-Molecule NOX Inhibitors: ROS-Generating NADPH Oxidases as Therapeutic Targets

Jaquet

Scapozza

Clark

et al. 2009

Antioxidants & Redox Signaling

229

197

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NOX NADPH oxidases are electron-transporting membrane enzymes whose primary function is the generation of reactive oxygen species (ROS). ROS produced by NOX enzymes show a variety of biologic functions, such as microbial killing, blood pressure regulation, and otoconia formation. Strong evidence suggests that NOX enzymes are major contributors to oxidative damage in pathologic conditions. Blocking the undesirable actions of NOX enzymes, therefore, is a therapeutic strategy for treating oxidative stress-related pathologies, such as ischemia/reperfusion tissue injury, and neurodegenerative and metabolic diseases. Most currently available NOX inhibitors have low selectivity, potency, and bioavailability, precluding a pharmacologic demonstration of NOX as therapeutic targets in vivo. This review has two main purposes. First, we describe a systematic approach that we believe should be followed in the search for truly selective NOX inhibitors. Second, we present a critical review of small-molecule NOX inhibitors described over the last two decades, including recently published patents from the pharmaceutical industry. Structures, activities, and in vitro/in vivo specificity of these NOX inhibitors are discussed. We conclude that NOX inhibition is a pertinent and promising novel pharmacologic concept, but that major efforts will be necessary to develop specific NOX inhibitors suited for clinical application.

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Mycophenolic Acid Is a New Nox2 Inhibitor

Cited by 7 publications

References 7 publications

Programmed Death-1 Controls T Cell Survival by Regulating Oxidative Metabolism

Programmed Death-1 Controls T Cell Survival by Regulating Oxidative Metabolism

Endothelin-1 impairs coronary arteriolar dilation: Role of p38 kinase-mediated superoxide production from NADPH oxidase

Small-Molecule NOX Inhibitors: ROS-Generating NADPH Oxidases as Therapeutic Targets

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