Iron chelation inhibits the development of pulmonary vascular remodeling

Wong, Chi‐Ming; Preston, Ioana R.; Hill, Nicholas S.; Suzuki, Yuichiro

doi:10.1016/j.freeradbiomed.2012.08.576

Cited by 42 publications

(32 citation statements)

References 46 publications

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“…We previously reported that protein carbonylation mediates cell signaling in response to receptor activation by ligands such as endothelin-1 and PDGF [11-13,27]. However, IL-22 signaling may not utilize protein carbonylation for STAT3 activation, since the phosphorylation of STAT3 occurs 10 min after the IL-22 stimulation, while most proteins are not carbonylated until 30 min.…”

Section: Discussionmentioning

confidence: 99%

IL-22 activates oxidant signaling in pulmonary vascular smooth muscle cells

Bansal

Das

Hsieh

et al. 2013

Cellular Signalling

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Reactive oxygen species (ROS) mediate cell-signaling processes in response to various ligands and play important roles in the pathogenesis of cardiovascular diseases. The present study reports that interleukin-22 (IL-22) elicits signal transduction in vascular smooth muscle cells (SMCs) through a ROS-dependent mechanism. We find that pulmonary artery SMCs express IL-22 receptor alpha 1 and that IL-22 activates STAT3 through this receptor. IL-22-induced signaling is found to be mediated by NADPH oxidase, as indicated by the observations that the inhibition and siRNA knock-down of this enzyme inhibit IL-22 signaling. IL-22 triggers the oxidative modifications of proteins through protein carbonylation and protein glutathionylation. Mass spectrometry identified some proteins that are carbonylated in response to IL-22 stimulation, including α-enolase, heat shock cognate 71 kDa protein, mitochondrial 60 kDa heat shock protein, and cytoplasmic 2 actin and determined that α-tubulin is glutathionylated. Protein glutathionylation and STAT3 phosphorylation are enhanced by the siRNA knock-down of glutaredoxin, while IL-22-mediated STAT3 phosphorylation is suppressed by knocking down thioredoxin interacting protein, an inhibitor of thioredoxin. IL-22 is also found to promote the growth of SMCs via NADPH oxidase. In rats, pulmonary hypertension is found to be associated with increased smooth muscle IL-22 expression. These results show that IL-22 promotes the growth of pulmonary vascular SMCs via a signaling mechanism that involves NADPH oxidase-dependent oxidation.

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Section: Discussionmentioning

confidence: 99%

IL-22 activates oxidant signaling in pulmonary vascular smooth muscle cells

Bansal

Das

Hsieh

et al. 2013

Cellular Signalling

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“…Iron chelation has been shown to attenuate hypoxia-induced PH, pulmonary vascular remodeling and right ventricular hypertrophy in rats. In addition, carbonylation of proteins was increased in hypoxia-induced rats as well in the plasma of the patients with PAH indicative of oxidative stress[178]. Furthermore, PH in patients with idiopathic pulmonary fibrosis was shown to correlate with iron deposition in alveolar spaces[179].…”

Section: Iron Homeostasis and Pahmentioning

confidence: 99%

Hematological disorders and pulmonary hypertension

Mathew

Huang

et al. 2016

WJC

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Pulmonary hypertension (PH), a serious disorder with a high morbidity and mortality rate, is known to occur in a number of unrelated systemic diseases. Several hematological disorders such as sickle cell disease, thalassemia and myeloproliferative diseases develop PH which worsens the prognosis. Associated oxidant injury and vascular inflammation cause endothelial damage and dysfunction. Pulmonary vascular endothelial damage/dysfunction is an early event in PH resulting in the loss of vascular reactivity, activation of proliferative and antiapoptotic pathways leading to vascular remodeling, elevated pulmonary artery pressure, right ventricular hypertrophy and premature death. Hemolysis observed in hematological disorders leads to free hemoglobin which rapidly scavenges nitric oxide (NO), limiting its bioavailability, and leading to endothelial dysfunction. In addition, hemolysis releases arginase into the circulation which converts L-arginine to ornithine, thus bypassing NO production. Furthermore, treatments for hematological disorders such as immunosuppressive therapy, splenectomy, bone marrow transplantation, and radiation have been shown to contribute to the development of PH. Recent studies have shown deregulated iron homeostasis in patients with cardiopulmonary diseases including pulmonary arterial hypertension (PAH). Several studies have reported low iron levels in patients with idiopathic PAH, and iron deficiency is an important risk factor. This article reviews PH associated with hematological disorders and its mechanism; and iron homeostasis and its relevance to PH.

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“…23,24 For example, in the monocrotaline model of PAH in SpragueDawley rats, dietary iron restriction has been shown to attenuate PA vascular remodeling and RV failure. 23 In that study by Naito et al, 23 an iron-deficient diet was initiated 1 day after monocrotaline injection and resulted in decreased PA wall thickness and a modest decrease in RV systolic pressures.…”

Section: Sutendra and Bonnet The Iron Paradigm Of Pah 1637mentioning

confidence: 99%