Hypoxia induces Kv channel current inhibition by increased NADPH oxidase-derived reactive oxygen species

Mittal, Manish; Gu, Xiang; Pak, Oleg; Pamenter, Matthew E.; Haag, Daniela; Fuchs, D. Beate; Schermuly, Ralph Theo; Ghofrani, Hossein Ardeschir; Brandes, Ralf P.; Seeger, Werner; Grimminger, Friedrich; Haddad, Gabriel G.; Weißmann, Norbert

doi:10.1016/j.freeradbiomed.2011.12.004

Cited by 66 publications

(69 citation statements)

References 54 publications

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“…One of these processes is ROS production by NADPH oxidases [91,115,116]. MARSHALL et al [115] first described a NADPH oxidase in pulmonary arteries and isolated PASMCs and their data suggested increased superoxide production by this NADPH oxidase under hypoxic conditions.…”

Section: Nadph Oxidases As Ros Sourcesmentioning

confidence: 99%

Oxygen sensing and signal transduction in hypoxic pulmonary vasoconstriction

et al. 2015

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Number 11 in the series "Physiology in respiratory medicine" Edited by R. Naeije, D. Chemla, A. Vonk-Noordegraaf and A.T. Dinh-Xuan Affiliation: Excellence Cluster Cardiopulmonary System, University of Giessen Lung Center, German Center for Lung Research (DZL), Justus-Liebig-University, Giessen, Germany.Correspondence: Norbert Weissmann, Excellence Cluster Cardiopulmonary System, University of Giessen Lung Center, German Center for Lung Research (DZL), Justus-Liebig-University, 35392 Giessen, Germany. E-mail: Norbert.Weissmann@innere.med.uni-giessen.de ABSTRACT Hypoxic pulmonary vasoconstriction (HPV), also known as the von Euler-Liljestrand mechanism, is an essential response of the pulmonary vasculature to acute and sustained alveolar hypoxia. During local alveolar hypoxia, HPV matches perfusion to ventilation to maintain optimal arterial oxygenation. In contrast, during global alveolar hypoxia, HPV leads to pulmonary hypertension. The oxygen sensing and signal transduction machinery is located in the pulmonary arterial smooth muscle cells (PASMCs) of the pre-capillary vessels, albeit the physiological response may be modulated in vivo by the endothelium. While factors such as nitric oxide modulate HPV, reactive oxygen species (ROS) have been suggested to act as essential mediators in HPV. ROS may originate from mitochondria and/or NADPH oxidases but the exact oxygen sensing mechanisms, as well as the question of whether increased or decreased ROS cause HPV, are under debate. ROS may induce intracellular calcium increase and subsequent contraction of PASMCs via direct or indirect interactions with protein kinases, phospholipases, sarcoplasmic calcium channels, transient receptor potential channels, voltage-dependent potassium channels and L-type calcium channels, whose relevance may vary under different experimental conditions. Successful identification of factors regulating HPV may allow development of novel therapeutic approaches for conditions of disturbed HPV. @ERSpublications ROS originating from mitochondria and/or NADPH oxidases may initiate HPV but exact signalling mechanisms are unclear http://ow.ly/SkaGC

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Section: Nadph Oxidases As Ros Sourcesmentioning

confidence: 99%

Oxygen sensing and signal transduction in hypoxic pulmonary vasoconstriction

et al. 2015

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“…While much of the evidence supports a role for NOX4 in the pathogenesis of PH (183,184), evidence suggests that NOX2 is also involved. Obstructive sleep apnea, characterized by intermittent periods of hypoxia, is a risk factor for the development of PH.…”

Section: Vascular Diseasesmentioning

confidence: 99%

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

Diebold

Smith

Yang

et al. 2015

Antioxidants & Redox Signaling

102

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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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“…23 Of note, NOX and iNOS have been implicated as pivotal regulators of ROS generation in obese adipose tissue. 24 Several reports demonstrate increments in the expression of NADPH oxidase subunits in WAT of KKAy obese Figure 1. Roles of G6PD in the regulation of cellular metabolisms.…”

Section: Introductionmentioning

confidence: 99%

The role of glucose-6-phosphate dehydrogenase in adipose tissue inflammation in obesity

et al. 2017

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Obesity is closely associated with metabolic diseases including type 2 diabetes. One hallmark characteristics of obesity is chronic inflammation that is coordinately controlled by complex signaling networks in adipose tissues. Compelling evidence indicates that reactive oxygen species (ROS) and its related signaling pathways play crucial roles in the progression of chronic inflammation in obesity. The pentose phosphate pathway (PPP) is an anabolic pathway that utilizes the glucoses to generate molecular building blocks and reducing equivalents in the form of NADPH. In particular, NADPH acts as one of the key modulators in the control of ROS through providing an electron for both ROS generation and scavenging. Recently, we have reported that glucose-6-phosphate dehydrogenase (G6PD), a rate-limiting enzyme of the PPP, is implicated in adipose tissue inflammation and systemic insulin resistance in obesity. Mechanistically, G6PD potentiates generation of ROS that augments pro-inflammatory responses in adipose tissue macrophages, leading to systemic insulin resistance. Here, we provide an overview of cell type-specific roles of G6PD in the regulation of ROS balance as well as additional details on the significance of G6PD that contributes to pro-oxidant NADPH generation in obesity-related chronic inflammation and insulin resistance.

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Hypoxia induces Kv channel current inhibition by increased NADPH oxidase-derived reactive oxygen species

Cited by 66 publications

References 54 publications

Oxygen sensing and signal transduction in hypoxic pulmonary vasoconstriction

Oxygen sensing and signal transduction in hypoxic pulmonary vasoconstriction

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

The role of glucose-6-phosphate dehydrogenase in adipose tissue inflammation in obesity

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