Reactive Oxygen Species-Reducing Strategies Improve Pulmonary Arterial Responses to Nitric Oxide in Piglets with Chronic Hypoxia-Induced Pulmonary Hypertension

Fike, Candice D.; Dikalova, Anna; Slaughter, James C.; Kaplowitz, Mark R.; Zhang, Y.; Aschner, Judy L.

doi:10.1089/ars.2012.4823

Cited by 37 publications

(37 citation statements)

References 49 publications

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“…shown in several models of pulmonary hypertension (4,13,15,26,35,40). Consistent with this possibility, CH decreased Cu/Zn SOD1 (cytosolic) and Cu/Zn SOD3 (extracellular) protein expression (Fig.…”

Section: Ch Decreases Sod Expression and Activitysupporting

confidence: 79%

“…In contrast, CH has been shown to decrease H 2 O 2 levels in several different species (6,13,40). Various models of pulmonary hypertension are associated with a dysregulation of superoxide dismutase (SOD), and possibly other antioxidant pathways, that could lead to lowering of H 2 O 2 levels (4,6,13,15,40). However, neither the mechanisms by which CH mediates this decrease in H 2 O 2 nor the importance of this response to regulation of pulmonary arterial smooth muscle calcium homeostasis are clearly defined.…”

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confidence: 99%

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Chronic hypoxia limits H₂O₂-induced inhibition of ASIC1-dependent store-operated calcium entry in pulmonary arterial smooth muscle

Plomaritas

Herbert

Yellowhair

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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Our laboratory shows that acid-sensing ion channel 1 (ASIC1) contributes to the development of hypoxic pulmonary hypertension by augmenting store-operated Ca(2+) entry (SOCE) that is associated with enhanced agonist-induced vasoconstriction and arterial remodeling. However, this enhanced Ca(2+) influx following chronic hypoxia (CH) is not dependent on an increased ASIC1 protein expression in pulmonary arterial smooth muscle cells (PASMC). It is well documented that hypoxic pulmonary hypertension is associated with changes in redox potential and reactive oxygen species homeostasis. ASIC1 is a redox-sensitive channel showing increased activity in response to reducing agents, representing an alternative mechanism of regulation. We hypothesize that the enhanced SOCE following CH results from removal of an inhibitory effect of hydrogen peroxide (H2O2) on ASIC1. We found that CH increased PASMC superoxide (O2 (·-)) and decreased rat pulmonary arterial H2O2 levels. This decrease in H2O2 is a result of decreased Cu/Zn superoxide dismutase expression and activity, as well as increased glutathione peroxidase (GPx) expression and activity following CH. Whereas H2O2 inhibited ASIC1-dependent SOCE in PASMC from control and CH animals, addition of catalase augmented ASIC1-mediated SOCE in PASMC from control rats but had no further effect in PASMC from CH rats. These data suggest that, under control conditions, H2O2 inhibits ASIC1-dependent SOCE. Furthermore, H2O2 levels are decreased following CH as a result of diminished dismutation of O2 (·-) and increased H2O2 catalysis through GPx-1, leading to augmented ASIC1-dependent SOCE.

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Section: Ch Decreases Sod Expression and Activitysupporting

confidence: 79%

mentioning

confidence: 99%

Chronic hypoxia limits H₂O₂-induced inhibition of ASIC1-dependent store-operated calcium entry in pulmonary arterial smooth muscle

Plomaritas

Herbert

Yellowhair

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…A dysfunctional EDNOsGC-cGMP-PKG signaling pathway constitutes one of the most fundamental and initial changes in the development of PH (1,33), resulting from aberrant expression of eNOS (34), reduced NO production caused by eNOS uncoupling (35)(36)(37)(38), diminished NO bioavailability caused by oxidative stress (39,40), diminished activities of sGC (41,42) and PKG (26,(43)(44)(45)(46), and augmented activity of phosphodiesterase type 5 (47).…”

Section: Edno As a Paracrine Regulatormentioning

confidence: 99%

“…ET-1 levels are increased in the lungs and plasma of patients with PAH as well as in the lungs of rats and fetal lambs with PH (78)(79)(80). The increased ET-1 levels may result in part from diminished inhibition of NO caused by reduced NO production and bioavailability (35,37,39,40). The reduced NO production may also result from the decreased gene expression and protein levels of ET B that occur in PH (80)(81)(82).…”

Section: Edno As a Paracrine Regulatormentioning

confidence: 99%

Endothelial and Smooth Muscle Cell Interactions in the Pathobiology of Pulmonary Hypertension

Gao

Chen

Raj

2016

Am J Respir Cell Mol Biol

107

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In the pulmonary vasculature, the endothelial and smooth muscle cells are two key cell types that play a major role in the pathobiology of pulmonary vascular disease and pulmonary hypertension. The normal interactions between these two cell types are important for the homeostasis of the pulmonary circulation, and any aberrant interaction between them may lead to various disease states including pulmonary vascular remodeling and pulmonary hypertension. It is well recognized that the endothelial cell can regulate the function of the underlying smooth muscle cell by releasing various bioactive agents such as nitric oxide and endothelin-1. In addition to such paracrine regulation, other mechanisms exist by which there is cross-talk between these two cell types, including communication via the myoendothelial injunctions and information transfer via extracellular vesicles. Emerging evidence suggests that these nonparacrine mechanisms play an important role in the regulation of pulmonary vascular tone and the determination of cell phenotype and that they are critically involved in the pathobiology of pulmonary hypertension.Keywords: paracrine; myoendothelial injunction; microvesicles; vasoconstriction; vascular remodelingIn the pulmonary vasculature, endothelial cells (ECs) and smooth muscle cells (SMCs) are the key cell types involved in the regulation of vessel diameter in most of the pulmonary vascular tree and thereby they regulate pulmonary arterial pressure and total vascular resistance. ECs, which are strategically located as the innermost layer of the blood vessel and are in contact with the circulating blood, exert a delicate and constant influence on the underlying vascular smooth muscle cells (VSMCs). It is well recognized that the regulation of pulmonary vasoreactivity by the endothelium is predominantly accomplished by paracrine signaling through the release of various vasoactive agents such as nitric oxide (NO), endothelin-1 (ET-1) (1-3), and others (4-8). However, there is increasing evidence that the relationship between the EC and the SMC is not a simple one-way interaction from the endothelium to the SMC; rather, there are complicated interactions between them (9-11). Moreover, the communication patterns are not limited to paracrine signaling; cross-talk through myoendothelial gap junctions (MEJs), extracellular vesicles (EVs), and other mechanisms is critically involved (12)(13)(14)(15)(16)(17)(18)(19)(20). These mechanisms operate in a complicated but co-ordinated manner to maintain the homeostasis of the pulmonary circulation. Under pathological conditions, the interaction between ECs and VSMCs may be chronically altered so that a sustained increase in vasocontractility and abnormal vascular proliferation develops, which leads to high pulmonary artery pressure, vascular remodeling, right ventricular hypertrophy, and the clinical condition, pulmonary hypertension (PH) (1,(21)(22)(23)(24). This article discusses the recent progress in our knowledge of the interactions between ECs and SMCs thr...

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“…Furthermore, up to 40% of infants do not respond or sustain a response to inhaled NO (4), an effect that may in part be mediated by the NO scavenging effects of ROS, which can divert NO from therapeutic signaling to deleterious reactive nitrogen species injury (with formation of nitrogen dioxide or peroxynitrite, for example). As supported by published reports, including some of the articles in this Forum of Pulmonary Hypertension, antioxidants may be particularly promising for the treatment of neonatal pulmonary hypertension, including PPHN (8) as well as pulmonary hypertension associated with bronchopulmonary dysplasia, which is emerging as a relatively common complication of preterm birth (2). The currently available data support the clear need for randomized clinical trials to investigate antioxidant therapies for these populations of patients.…”

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confidence: 93%

Antioxidant Therapy for the Treatment of Pulmonary Hypertension

Suzuki

Steinhorn²,

Gladwin

2013

Antioxidants & Redox Signaling

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Substantial experimental evidence suggests the usefulness of antioxidants for the treatment of various forms of pulmonary hypertension. However, no recommendations have yet been made if patients with pulmonary hypertension should receive pharmacologic and/or dietary antioxidants. Our understanding of antioxidants has evolved greatly over the last two decades, from the primitive use of natural antioxidant vitamins to the modulation of vascular oxidases, such as NAD(P)H oxidases. These oxidases and their products not only regulate pulmonary vascular tone and intimal and smooth muscle thickening, but also modulate the adaptation of the right ventricle to increased afterload. It is important that well-designed randomized clinical trials be conducted to test the importance of oxidase-reactive oxygen species activation in the pathogenesis and treatment of pulmonary hypertension. The purpose of this Forum on Pulmonary Hypertension is to summarize the available preclinical information, which may aid in designing and conducting future randomized clinical trials for evaluating the efficacy of antioxidants for the treatment of pulmonary hypertension. The complexity of oxidative pathways contributed to the tremendous difficulties and challenges in selecting agents, doses, and designing clinical trials. Further studies using human, animal, and cell culture models may be needed to define optimal trials. This Forum on Pulmonary Hypertension should stimulate new thinking and provide essential background information to better define the challenges of developing successful randomized clinical trials in the near future. Antioxid. Redox Signal. 18, 1723-1726. Many studies suggest a pathogenic role for reactive oxygen species (ROS) and oxidative stress in pulmonary arterial hypertension (PAH). Experimental animal models have demonstrated the effectiveness of various antioxidant therapeutics in modulating PAH development and their progression. Moreover, PAH patients have increased oxidative stress and upregulation of critical oxidase enzyme systems. Despite substantial experimental evidence suggesting the usefulness of antioxidants for the treatment of pulmonary hypertension at various aspects of this disease (Fig. 1), it is unclear if patients with pulmonary hypertension should receive pharmacologic and/or dietary antioxidants. Furthermore, our conceptual understanding of antioxidants has evolved greatly over the last two decades, from the primitive use of natural antioxidant vitamins, with very low radical reactivities, to the current emphasis on the modulation of vascular oxidases, such as xanthine oxidase, NAD(P)H oxidases, and pathological mitochondrial ROS formation. These oxidases and their products appear to regulate not only pulmonary vascular tone and maladaptive intimal and smooth muscle proliferation, but also modulate the adaptation of the right ventricle to chronically increased afterload stress. It is important that well-designed randomized clinical trials be conducted to test the importance of oxidase-ROS acti...

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Reactive Oxygen Species-Reducing Strategies Improve Pulmonary Arterial Responses to Nitric Oxide in Piglets with Chronic Hypoxia-Induced Pulmonary Hypertension

Abstract: Strategies aimed at reducing ROS merit further evaluation and consideration as therapeutic approaches to improve responses to iNO in infants with chronic pulmonary hypertension.

Cited by 37 publications

References 49 publications

Chronic hypoxia limits H₂O₂-induced inhibition of ASIC1-dependent store-operated calcium entry in pulmonary arterial smooth muscle

Chronic hypoxia limits H₂O₂-induced inhibition of ASIC1-dependent store-operated calcium entry in pulmonary arterial smooth muscle

Endothelial and Smooth Muscle Cell Interactions in the Pathobiology of Pulmonary Hypertension

Antioxidant Therapy for the Treatment of Pulmonary Hypertension

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Reactive Oxygen Species-Reducing Strategies Improve Pulmonary Arterial Responses to Nitric Oxide in Piglets with Chronic Hypoxia-Induced Pulmonary Hypertension

Abstract: Strategies aimed at reducing ROS merit further evaluation and consideration as therapeutic approaches to improve responses to iNO in infants with chronic pulmonary hypertension.

Cited by 37 publications

References 49 publications

Chronic hypoxia limits H2O2-induced inhibition of ASIC1-dependent store-operated calcium entry in pulmonary arterial smooth muscle

Chronic hypoxia limits H2O2-induced inhibition of ASIC1-dependent store-operated calcium entry in pulmonary arterial smooth muscle

Endothelial and Smooth Muscle Cell Interactions in the Pathobiology of Pulmonary Hypertension

Antioxidant Therapy for the Treatment of Pulmonary Hypertension

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Product

Resources

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Chronic hypoxia limits H₂O₂-induced inhibition of ASIC1-dependent store-operated calcium entry in pulmonary arterial smooth muscle

Chronic hypoxia limits H₂O₂-induced inhibition of ASIC1-dependent store-operated calcium entry in pulmonary arterial smooth muscle