Small-Molecule Inhibitors of NADPH Oxidase 4

Borbély, Gábor; Szabadkai, István; Horváth, Zoltán; Marko, Peter; Varga, Zoltán; Breza, Nóra; Baska, Ferenc; Vántus, Tibor; Huszár, Mónika; Geiszt, Miklós; Hunyady, László; Buday, László; Őrfi, László; Kéri, Gÿorgý

doi:10.1021/jm1004368

Cited by 52 publications

(42 citation statements)

References 22 publications

(40 reference statements)

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“…However, until recently, specific pharmacological inhibitors of NADPH oxidase were not available. For example, diphenyleneiodonium is commonly used as a synthetic NADPH oxidase inhibitor (34). However, diphenyleneiodonium nonspecifically inhibits the action of multiple flavoprotein dehydrogenases (35).…”

Section: Discussionmentioning

confidence: 99%

The Nox4 Inhibitor GKT137831 Attenuates Hypoxia-Induced Pulmonary Vascular Cell Proliferation

Green

Murphy

Kang

et al. 2012

Am J Respir Cell Mol Biol

134

147

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Increased NADP reduced (NADPH) oxidase 4 (Nox4) and reduced expression of the nuclear hormone receptor peroxisome proliferator-activated receptor g (PPARg) contribute to hypoxiainduced pulmonary hypertension (PH). To examine the role of Nox4 activity in pulmonary vascular cell proliferation and PH, the current study used a novel Nox4 inhibitor, GKT137831, in hypoxiaexposed human pulmonary artery endothelial or smooth muscle cells (HPAECs or HPASMCs) in vitro and in hypoxia-treated mice in vivo. HPAECs or HPASMCs were exposed to normoxia or hypoxia (1% O 2 ) for 72 hours with or without GKT137831. Cell proliferation and Nox4, PPARg, and transforming growth factor (TGF)b1 expression were measured. C57Bl/6 mice were exposed to normoxia or hypoxia (10% O 2 ) for 3 weeks with or without GKT137831 treatment during the final 10 days of exposure. Lung PPARg and TGF-b1 expression, right ventricular hypertrophy (RVH), right ventricular systolic pressure (RVSP), and pulmonary vascular remodeling were measured. GKT137831 attenuated hypoxia-induced H 2 O 2 release, proliferation, and TGF-b1 expression and blunted reductions in PPARg in HPAECs and HPASMCs in vitro. In vivo GKT137831 inhibited hypoxia-induced increases in TGF-b1 and reductions in PPARg expression and attenuated RVH and pulmonary artery wall thickness but not increases in RVSP or muscularization of small arterioles. This study shows that Nox4 plays a critical role in modulating proliferative responses of pulmonary vascular wall cells. Targeting Nox4 with GKT137831 provides a novel strategy to attenuate hypoxiainduced alterations in pulmonary vascular wall cells that contribute to vascular remodeling and RVH, key features involved in PH pathogenesis.Keywords: rosiglitazone; PPARg; TGF-b; pulmonary hypertension Pulmonary hypertension (PH) is a progressive disorder associated with significant morbidity and mortality. Although recent therapeutic advances have improved survival for patients with PH, the prognosis remains poor (1). The pathobiology of PH is complex, and factors that contribute to endothelial dysfunction have been implicated in pathogenesis (2, 3). Among these factors, NADP reduced (NADPH) oxidase enzymes that produce reactive oxygen species (ROS) contribute to the development of a variety of vascular diseases, such as atherosclerosis (4) and systemic (5) and pulmonary hypertension (6). NADPH oxidases catalyze the reduction of molecular oxygen to generate superoxide (O 2 .2 ), hydrogen peroxide (H 2 O 2 ), or secondary oxidants (7). Seven isoforms of the catalytic moiety of the nonphagocytic NADPH oxidase enzyme have been described (Nox1-5, Duox1-2). These subunits are homologous to the catalytic moiety of the prototype phagocytic NADPH oxidase Nox2 (or gp91 phox ) but differ from each other regarding cellular localization, tissue distribution, regulation, activation, and expression (7,8). For example, although both Nox1 and Nox4 are expressed in vascular smooth muscle cells (VSMCs), they are targeted to discreet intracellular locations, are differe...

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Section: Discussionmentioning

confidence: 99%

The Nox4 Inhibitor GKT137831 Attenuates Hypoxia-Induced Pulmonary Vascular Cell Proliferation

Green

Murphy

Kang

et al. 2012

Am J Respir Cell Mol Biol

134

147

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“…Thus, selective targeting of Nox2 may provide a novel therapeutic strategy for mitigation of ROS/RNS and cardiotoxic side effects, while maximizing its antitumor efficacy (56). To date, only a limited number of Nox isoform-selective inhibitors are available (57,58). This is due in part to serious limitations of the existing ROS/RNS assays as described below.…”

Section: Hts/ros/rns Assay-ros/rnsmentioning

confidence: 99%

Mitigation of NADPH Oxidase 2 Activity as a Strategy to Inhibit Peroxynitrite Formation

Zielonka

VerPlank

et al. 2016

Journal of Biological Chemistry

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Using high throughput screening-compatible assays for superoxide and hydrogen peroxide, we identified potential inhibitors of the NADPH oxidase (Nox2) isoform from a small library of bioactive compounds. By using multiple probes (hydroethidine, hydropropidine, Amplex Red, and coumarin boronate) with well defined redox chemistry that form highly diagnostic marker products upon reaction with superoxide (O 2 . ),

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“…In a recent study, Borbely et al (16) showed the methodical development of derivatives of primary hits obtained by an HTS campaign that searched for smallmolecule inhibitors of Nox4. The most potent compounds belong to the following core structures: oxalyl hydrazides, flavonoids, oxindoles, benzoquinolines, and benzothiophenes.…”

Section: Ebselenmentioning

confidence: 99%

The Quest for Selective Nox Inhibitors and Therapeutics: Challenges, Triumphs and Pitfalls

Cifuentes-Pagano

Meijles

Pagano

2014

Antioxidants & Redox Signaling

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Small-Molecule Inhibitors of NADPH Oxidase 4

Cited by 52 publications

References 22 publications

The Nox4 Inhibitor GKT137831 Attenuates Hypoxia-Induced Pulmonary Vascular Cell Proliferation

The Nox4 Inhibitor GKT137831 Attenuates Hypoxia-Induced Pulmonary Vascular Cell Proliferation

Mitigation of NADPH Oxidase 2 Activity as a Strategy to Inhibit Peroxynitrite Formation

The Quest for Selective Nox Inhibitors and Therapeutics: Challenges, Triumphs and Pitfalls

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