Hypoxia-Dependent Reactive Oxygen Species Signaling in the Pulmonary Circulation: Focus on Ion Channels

Veit, Florian; Pak, Oleg; Brandes, Ralf P.; Weißmann, Norbert

doi:10.1089/ars.2014.6234

Cited by 53 publications

(48 citation statements)

References 181 publications

(151 reference statements)

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“…Moreover, oxidants [94,95,97] as well as antioxidants [60,98] inhibited HPV. This finding might be due to the fact that these substances can cause both activation and inhibition of ion channel activity under different conditions [99]. Additionally, these agents may exert a nonspecific vasodilatory effect on the pulmonary vasculature, as shown for H 2 O 2 [94] or tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl) [98].…”

Section: Increased Mitochondrial Ros Release As a Trigger For Hpvmentioning

confidence: 99%

“…Hypothetically, ROS could interact directly with L-type calcium channels or activate them via membrane depolarisation by inhibition of K V channels, which was recently shown in endothelium-denuded pulmonary arteries [125]. Redox regulation of L-type calcium channels and K V channels has been recently summarised [99,142]. However, the hypothesis is limited by the fact that inhibition of L-type calcium channels or genetic deletion of K V channels only partially inhibited HPV [86,[143][144][145].…”

Section: Downstream Targets Of Rosmentioning

confidence: 99%

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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: Increased Mitochondrial Ros Release As a Trigger For Hpvmentioning

confidence: 99%

Section: Downstream Targets Of Rosmentioning

confidence: 99%

Oxygen sensing and signal transduction in hypoxic pulmonary vasoconstriction

et al. 2015

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“…The complex signaling mechanism behind HPV has not yet been fully elucidated; however, the available data suggest that several intermediates are critical. Besides TRPC6, other ion channels have been implicated in mediating HPV, including TRPV4 , voltage-gated potassium channels, and obviously voltage-gated calcium channels in vascular smooth muscle cells (Veit et al, 2015). Therefore, selectivity tests were extended to cover the Ca 21 -permeable TRPV4 and CaV 1.2 .…”

Section: Larixyl Acetate Is a Trpc6 Inhibitormentioning

confidence: 99%

Identification and Validation of Larixyl Acetate as a Potent TRPC6 Inhibitor

et al. 2015

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Classical or canonical transient receptor potential 6 (TRPC6), a nonselective and Ca 21 -permeable cation channel, mediates pathophysiological responses within pulmonary and renal diseases that are still poorly controlled by current medication. Thus, controlling TRPC6 activity may provide a promising and challenging pharmacological approach. Recently identified chemical entities have demonstrated that TRPC6 is pharmacologically targetable. However, isotype-selectivity with regard to its closest relative, TRPC3, is difficult to achieve. Reasoning that balsams, essential oils, or incense materials that are traditionally used for inhalation may contain biologic activities to block TRPC6 activity, we embarked on a natural compound strategy to identify new TRPC6-blocking chemical entities. Within several preparations of plant extracts, a strong TRPC6-inhibitory activity was found in conifer balsams. The biologic activity was associated with nonvolatile resins, but not with essential oils. Of various conifers, the larch balsam was unique in displaying a marked TRPC6-prevalent mode of action. By testing the main constituents of larch resin, we identified larixol and larixyl acetate as blockers of Ca 21 entry and ionic currents through diacylglycerol-or receptor-activated recombinant TRPC6 channels, exhibiting approximately 12-and 5-fold selectivity compared with its closest relatives TRPC3 and TRPC7, respectively. No significant inhibition of more distantly related TRPV or TRPM channels was seen. The potent inhibition of recombinant TRPC6 by larixyl acetate (IC 50 5 0.1-0.6 mM) was confirmed for native TRPC6-like [Ca 21 ] i signals in diacylglycerol-stimulated rat pulmonary artery smooth muscle cells. In isolated mouse lungs, larix-6-yl monoacetate (CAS 4608-49-5; larixyl acetate; 5 mM) prevented acute hypoxiainduced vasoconstriction. We conclude that larch-derived labdane-type diterpenes are TRPC6-selective inhibitors and may represent a starting point for pharmacological TRPC6 modulation within experimental therapies.

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“…Additionally, a critical role for members of the TRPC family in regulating Ca 2ϩ influx in the setting of various injurious stimuli (such as thrombin and LPS) in both pulmonary artery and mouse lung microvascular endothelial cells (MLMVECs) has been established (2,34,53,55,56). ROS and increased [Ca 2ϩ ] i may in fact be mechanistically linked; ROS increased [Ca 2ϩ ] i in various tissues including the lung (40,60), but the specific channel responsible for ROSinduced Ca 2ϩ influx in the lung microvasculature is not known. While TRPs clearly play a major role in endothelial cell responses to various stimuli, little is known regarding the mechanisms by which the function of these channels is regulated in LMVECs.…”

mentioning

confidence: 99%

Hydrogen peroxide-induced calcium influx in lung microvascular endothelial cells involves TRPV4

Suresh

Servinsky

Reyes

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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In acute respiratory distress syndrome, both reactive oxygen species (ROS) and increased intracellular calcium ([Ca 2ϩ ]i) are thought to play important roles in promoting endothelial paracellular permeability, but the mechanisms linking ROS and [Ca 2ϩ ]i in microvascular endothelial cells are not known. In this study, we assessed the effect of hydrogen peroxide (H2O2) on [Ca 2ϩ ]i in mouse and human lung microvascular endothelial cells (MLMVEC and HLMVEC, respectively). We found that in both MLMVECs and HLMVECs, exogenously applied H2O2 increased [Ca 2ϩ ]i through Ca 2ϩ influx and that pharmacologic inhibition of the calcium channel transient receptor potential vanilloid 4 (TRPV4) attenuated the H2O2-induced Ca 2ϩ influx. Additionally, knockdown of TRPV4 in HLMVEC also attenuated calcium influx following H2O2 challenge. Administration of H2O2 or TRPV4 agonists decreased transmembrane electrical resistance (TER), suggesting increased barrier permeability. To explore the regulatory mechanisms underlying TRPV4 activation by ROS, we examined H2O2-induced Ca 2ϩ influx in MLMVECs and HLMVECs with either genetic deletion, silencing, or pharmacologic inhibition of Fyn, a Src family kinase. In both MLMVECs derived from mice deficient for Fyn and HLMVECs treated with either siRNA targeted to Fyn or the Src family kinase inhibitor SU-6656 for 24 or 48 h, the H 2O2-induced Ca 2ϩ influx was attenuated. Treatment with SU-6656 decreased the levels of phosphorylated, but not total, TRPV4 protein and had no effect on TRPV4 response to the external agonist, GSK1016790A. In conclusion, our data suggest that application of exogenous H2O2 increases [Ca 2ϩ ]i and decreases TER in microvascular endothelial cells via activation of TRPV4 through a mechanism that requires the Src kinase Fyn.

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Hypoxia-Dependent Reactive Oxygen Species Signaling in the Pulmonary Circulation: Focus on Ion Channels

Cited by 53 publications

References 181 publications

Oxygen sensing and signal transduction in hypoxic pulmonary vasoconstriction

Oxygen sensing and signal transduction in hypoxic pulmonary vasoconstriction

Identification and Validation of Larixyl Acetate as a Potent TRPC6 Inhibitor

Hydrogen peroxide-induced calcium influx in lung microvascular endothelial cells involves TRPV4

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