Heme oxygenase-1 induction modulates hypoxic pulmonary vasoconstriction through upregulation of ecSOD

Ahmad, Mansoor; Zhao, Xiangmin; Kelly, Melissa R.; Kandhi, Sharath; Pérez, Óscar; Abraham, Nader G.; Wolin, Michael S.

doi:10.1152/ajpheart.00315.2009

Cited by 22 publications

(34 citation statements)

References 23 publications

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“…Most of the data regarding the effect of heme on oxidative stress involves the anti-oxidant enzyme HO-1 (12,48). Interestingly, some antioxidant mechanisms of HO-1 on vascular cells require the production of extracellular SOD-1 (49,50). In the current study, neither the HO-1 inductor CoPPIX nor the inhibitor of HO-1 activity SnPPXI interfered with SOD activity, suggesting that the heme effect on SOD is not directly mediated by HO-1.…”

Section: Discussioncontrasting

confidence: 52%

Heme Impairs Prostaglandin E2 and TGF-β Production by Human Mononuclear Cells via Cu/Zn Superoxide Dismutase: Insight into the Pathogenesis of Severe Malaria

Andrade

Araújo-Santos

Luz

et al. 2010

The Journal of Immunology

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In many hemolytic disorders, such as malaria, the release of free heme has been involved in the triggering of oxidative stress and tissue damage. Patients presenting with severe forms of malaria commonly have impaired regulatory responses. Although intriguing, there is scarce data about the involvement of heme on the regulation of immune responses. In this study, we investigated the relation of free heme and the suppression of anti-inflammatory mediators such as PGE2 and TGF-β in human vivax malaria. Patients with severe disease presented higher hemolysis and higher plasma concentrations of Cu/Zn superoxide dismutase (SOD-1) and lower concentrations of PGE2 and TGF-β than those with mild disease. In addition, there was a positive correlation between SOD-1 concentrations and plasma levels of TNF-α. During antimalaria treatment, the concentrations of plasma SOD-1 reduced whereas PGE2 and TGF-β increased in the individuals severely ill. Using an in vitro model with human mononuclear cells, we demonstrated that the heme effect on the impairment of the production of PGE2 and TGF-β partially involves heme binding to CD14 and depends on the production of SOD-1. Aside from furthering the current knowledge about the pathogenesis of vivax malaria, the present results may represent a general mechanism for hemolytic diseases and could be useful for future studies of therapeutic approaches.

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Section: Discussioncontrasting

confidence: 52%

Heme Impairs Prostaglandin E2 and TGF-β Production by Human Mononuclear Cells via Cu/Zn Superoxide Dismutase: Insight into the Pathogenesis of Severe Malaria

Andrade

Araújo-Santos

Luz

et al. 2010

The Journal of Immunology

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“…In the paper in this issue of the ERJ [14], the SOD mimetic did not alter HPV; however, catalase increased HPV in hph-1 mice and heterozygotes, and tended to increase it in the wild-type mice. This suggests a vasodilator role for H 2 O 2 in the setting of HPV, a concept proposed in 1986 [24] and supported by recent observations in bovine pulmonary arteries [25].…”

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confidence: 71%

Superoxide dismutase: Master and Commander?

2010

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Inhaled nitric oxide (NO) has long been known to be an effective pulmonary vasodilator in the normal pulmonary vasculature. In the classical NO signalling pathway, it activates soluble guanylate cyclase in the cytoplasm of pulmonary artery smooth muscle cells, leading to the production of cyclic guanosine monophosphate (cGMP), which then activates protein kinase G (PKG). PKG, acting through several downstream targets, causes vasodilatation. In addition, NO acts through induction of post-translational changes, such as Snitrosylation of proteins with reactive thiols. NO levels are decreased in idiopathic pulmonary arterial hypertension (IPAH) [1,2], in patients with PAH secondary to anorectic agents [3] and in infants with persistent pulmonary hypertension of the newborn (PPHN) [4]. In part, NO is decreased because of the reduced endothelial NO synthase (eNOS) that has been reported in PAH and in PPHN [5,6]. More recently, an additional mechanism has been described. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase and IPAH patients have increased levels of ADMA in their blood and lungs [7]. ADMA is metabolised by dimethylarginine dimethylaminohydrolase (DDAH) 1 or DDAH2, two enzymes encoded by different genes. Although solid evidence supporting a role for DDAH2 in the degradation of lung ADMA is not available, DDAH1 gene deletion in vascular endothelial cells causes accumulation of ADMA in the lung tissue of mice [8]. Similarly, monocrotaline injection causes a decrease in lung DDAH1 expression and DDAH activity, leading to the accumulation of ADMA in rats, which may then contribute to the development of pulmonary hypertension [9]. The increased ADMA levels provide another mechanism to explain the decreased NO levels in PAH. It is also worth noting that in IPAH patients, higher ADMA plasma levels correlate with worse pulmonary haemodynamics and decreased survival [7].Given the reduced level of NO in PAH, it is not surprising that efforts have been made to increase endogenous NO production. Endothelial NO synthetase generates NO through the oxidation of L-arginine, using tetrahydrobiopterin (BH 4 ), oxygen, nicotinamide adenine dinucleotide phosphate (NADPH) and calcium/calmodulin as cofactors. Decreased availability of L-arginine or BH 4 can lead to uncoupling of NOS and production of superoxide anion (O 2 -). O 2 -production can also be increased in the lung through other mechanisms, such as NAD(P)H oxidase activity or mitochondrial metabolism.O 2 -in turn, can combine with NO to form peroxynitrite or, through the action of one of three classes of superoxide dismutase (SOD), generate hydrogen peroxide (H 2 O 2 ). Supplementation of L-arginine, either by intravenous infusion for 30 min [10] or orally for a week [11], produces modest decreases in pulmonary artery pressure (16 and 9%, respectively) and resistance (28 and 16%, respectively).Production of BH 4 requires the activity of GTP-cyclohydrolase 1 (GTP-CH1). The hyperphenylalaninemic mouse (hph-1) has a 90% reduction in GP...

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“…Uniform rings of mouse pulmonary arteries and BPA were placed in plastic scintillation minivials containing 5 M lucigenin in 1 ml of Krebs solution buffered with 10 mM HEPES-NaOH (pH 7.4). The chemiluminescence from superoxide was measured by a liquid scintillation counter (LS6000IC; Beckman Instruments, San Diego, CA) with a single active photomultiplier tube in a dark room using previously described methods (1). Background chemiluminescence in absence of the tissue was subtracted from subsequent measurements made in the presence of the pulmonary artery tissue.…”

Section: Methodsmentioning

confidence: 99%

Heme biosynthesis modulation via δ-aminolevulinic acid administration attenuates chronic hypoxia-induced pulmonary hypertension

Alhawaj

Patel

Kelly

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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Alhawaj R, Patel D, Kelly MR, Sun D, Wolin MS. Heme biosynthesis modulation via ␦-aminolevulinic acid administration attenuates chronic hypoxia-induced pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 308: L719 -L728, 2015. First published February 6, 2015 doi:10.1152/ajplung.00155.2014.-This study examines how heme biosynthesis modulation with ␦-aminolevulinic acid (ALA) potentially functions to prevent 21-day hypoxia (10% oxygen)-induced pulmonary hypertension in mice and the effects of 24-h organoid culture with bovine pulmonary arteries (BPA) with the hypoxia and pulmonary hypertension mediator endothelin-1 (ET-1), with a focus on changes in superoxide and regulation of micro-RNA 204 (miR204) expression by src kinase phosphorylation of signal transducer and activator of transcription-3 (STAT3). The treatment of mice with ALA attenuated pulmonary hypertension (assessed through echo Doppler flow of the pulmonary valve, and direct measurements of right ventricular systolic pressure and right ventricular hypertrophy), increases in pulmonary arterial superoxide (detected by lucigenin), and decreases in lung miR204 and mitochondrial superoxide dismutase (SOD2) expression. ALA treatment of BPA attenuated ET-1-induced increases in mitochondrial superoxide (detected by MitoSox), STAT3 phosphorylation, and decreases in miR204 and SOD2 expression. Because ALA increases BPA protoporphyrin IX (a stimulator of guanylate cyclase) and cGMP-mediated protein kinase G (PKG) activity, the effects of the PKG activator 8-bromo-cGMP were examined and found to also attenuate the ET-1-induced increase in superoxide. ET-1 increased superoxide production and the detection of protoporphyrin IX fluorescence, suggesting oxidant conditions might impair heme biosynthesis by ferrochelatase. However, chronic hypoxia actually increased ferrochelatase activity in mouse pulmonary arteries. Thus, a reversal of factors increasing mitochondrial superoxide and oxidant effects that potentially influence remodeling signaling related to miR204 expression and perhaps iron availability needed for the biosynthesis of heme by the ferrochelatase reaction could be factors in the beneficial actions of ALA in pulmonary hypertension. endothelin; ferrochelatase; guanylate cyclase; micro-RNA 204; superoxide CHRONIC HYPOXIA IS AN IMPORTANT factor in the development of pulmonary hypertension in diseases such as chronic obstructive pulmonary disease (COPD), sleep apnea, and mountain sickness (10,20). It is thought to promote pulmonary hypertension development through persistent pulmonary vasoconstriction and vascular remodeling (31). There is substantial evidence for increases in the generation of reactive oxygen species from sources including Nox oxidases and mitochondria having important roles in the development and/or progression of pulmonary hypertension caused by chronic hypoxia and other stimuli of this disease process (7,15,18,27,30). Pulmonary arterial generation of nitric oxide (NO) is normally thought to oppose this process of vasoconstriction ...

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Heme oxygenase-1 induction modulates hypoxic pulmonary vasoconstriction through upregulation of ecSOD

Cited by 22 publications

References 23 publications

Heme Impairs Prostaglandin E2 and TGF-β Production by Human Mononuclear Cells via Cu/Zn Superoxide Dismutase: Insight into the Pathogenesis of Severe Malaria

Heme Impairs Prostaglandin E2 and TGF-β Production by Human Mononuclear Cells via Cu/Zn Superoxide Dismutase: Insight into the Pathogenesis of Severe Malaria

Superoxide dismutase: Master and Commander?

Heme biosynthesis modulation via δ-aminolevulinic acid administration attenuates chronic hypoxia-induced pulmonary hypertension

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