scholarly journals Effects of nitrogen monoxide and carbon monoxide on molecular and cellular iron metabolism: mirror-image effector molecules that target iron

2003 ◽  
Vol 369 (3) ◽  
pp. 429-440 ◽  
Author(s):  
Ralph N. WATTS ◽  
Prem PONKA ◽  
Des R. RICHARDSON
Keyword(s):  
Carbon Monoxide ◽  
Nitrogen Monoxide ◽  
Preliminary Evidence ◽  
Mirror Image ◽  
Cellular Mechanisms ◽  
Iron Regulatory Proteins ◽  
Cellular Iron ◽  
Fe Complex ◽  
Oxide Synthase ◽  
Mrna Binding

Many effector functions of nitrogen monoxide (NO) and carbon monoxide (CO) are mediated through their high-affinity for iron (Fe). In this review, the roles of NO and CO are examined in terms of their effects on the molecular and cellular mechanisms involved in Fe metabolism. Both NO and CO avidly form complexes with a plethora of Fe-containing molecules. The generation of NO and CO is mediated by the nitric oxide synthase and haem oxygenase (HO) families of enzymes respectively. The effects of NO on Fe metabolism have been well characterized, whereas knowledge of the effects of CO remains within its infancy. In terms of the role of NO in Fe metabolism, one of the best characterized interactions includes its effect on the iron regulatory proteins. These molecules are mRNA-binding proteins that control the expression of the transferrin receptor 1 and ferritin, molecules that are involved in Fe uptake and storage respectively. Apart from this, activated macrophages impart their cytotoxic activity by generating NO, which results in marked Fe mobilization from tumour-cell targets. This deprives the cell of the Fe that is required for DNA synthesis and energy production. Considering that HO degrades haem, resulting in the release of CO, Fe(II) and biliverdin, it is suggested that a CO—Fe complex will form. This may account for the rapid Fe mobilization observed from macrophages after haemoglobin catabolism. Intriguingly, overexpression of HO results in cellular Fe mobilization, suggesting that CO has a similar effect to NO on Fe trafficking. Preliminary evidence suggests that, like NO, CO plays important roles in Fe metabolism.

scholarly journals Cloned, expressed rat cerebellar nitric oxide synthase contains stoichiometric amounts of heme, which binds carbon monoxide.

1992 ◽  
Vol 89 (23) ◽  
pp. 11141-11145 ◽  
Author(s):  
K. McMillan ◽  
D. S. Bredt ◽  
D. J. Hirsch ◽  
S. H. Snyder ◽  
J. E. Clark ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Carbon Monoxide ◽  
Nitric Oxide Synthase ◽  
Oxide Synthase

Overexpression of mitochondrial ferritin causes cytosolic iron depletion and changes cellular iron homeostasis

Blood ◽  
2005 ◽  
Vol 105 (5) ◽  
pp. 2161-2167 ◽  
Author(s):  
Guangjun Nie ◽  
Alex D. Sheftel ◽  
Sangwon F. Kim ◽  
Prem Ponka
Keyword(s):  
Iron Homeostasis ◽  
Rna Binding ◽  
Binding Activity ◽  
Intracellular Iron ◽  
Free Radical Damage ◽  
Iron Regulatory Proteins ◽  
Cellular Iron ◽  
Cellular Iron Uptake ◽  
A Cell ◽  
Cellular Iron Homeostasis

AbstractCytosolic ferritin sequesters and stores iron and, consequently, protects cells against iron-mediated free radical damage. However, the function of the newly discovered mitochondrial ferritin (MtFt) is unknown. To examine the role of MtFt in cellular iron metabolism, we established a cell line that stably overexpresses mouse MtFt under the control of a tetracycline-responsive promoter. The overexpression of MtFt caused a dose-dependent iron deficiency in the cytosol that was revealed by increased RNA-binding activity of iron regulatory proteins (IRPs) along with an increase in transferrin receptor levels and decrease in cytosolic ferritin. Consequently, the induction of MtFt resulted in a dramatic increase in cellular iron uptake from transferrin, most of which was incorporated into MtFt. The induction of MtFt caused a shift of iron from cytosolic ferritin to MtFt. In addition, iron inserted into MtFt was less available for chelation than that in cytosolic ferritin and the expression of MtFt was associated with decreased mitochondrial and cytosolic aconitase activities, the latter being consistent with the increase in IRP-binding activity. In conclusion, our results indicate that overexpression of MtFt causes a dramatic change in intracellular iron homeostasis and that shunting iron to MtFt likely limits its availability for active iron proteins.

Abstract 293: Mammalian Target of Rapamycin and Tristetraprolin Regulate Iron Homeostasis in Cardiac Cells

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Marina Bayeva ◽  
Arineh Khechaduri ◽  
Hossein Ardehali
Keyword(s):  
Energy Metabolism ◽  
Iron Homeostasis ◽  
Heart Function ◽  
Iron Regulation ◽  
Mrna Levels ◽  
Iron Regulatory Proteins ◽  
Regulatory Pathways ◽  
Genetic Knockout ◽  
Cellular Iron ◽  
Vital Functions

Introduction: Iron is essential for normal heart function, and disruption of iron homeostasis can lead to cardiomyopathy. However, our understanding of iron regulation on a cellular level is incomplete, with a single model involving iron regulatory proteins (IRP) described to date. Here, we report the existence of a parallel iron regulatory pathway by energy sensor mTOR and inflammatory mediator trsitetraprolin (TTP). Results: To examine the role of energy metabolism in the regulation of cellular iron, we used rapamycin to inhibit mTOR pathway in H9c2 cardiac myoblasts and mouse embryonic fibroblasts (MEFs). Rapamycin treatment significantly elevated cellular iron content through a coordinated reduction in iron import (transferrin receptor, TfR1) and iron export (ferroportin, Fpn1), leading to deceleration of iron flux and net iron accumulation. We found that the primary action of rapamycin was to reduce TfR1 through destabilization of its mRNA. Surprisingly, this effect was not mediated by IRP1/2, the “classical” sensors of cellular iron levels, as TfR1 mRNA levels were significantly reduced by rapamycin even in cells with the genetic knockout of IRP1 and IRP2. In yeast, a tandem zinc finger (TZF) protein Cth2 was found to conserve cellular iron in states of deficiency by preferentially degrading mRNA of non-essential iron-containing proteins thus reducing iron requirements and liberating iron for vital functions. We found that the mammalian TZF protein TTP, an established mediator of inflammation, was greatly induced by iron deficiency, enhanced degradation of iron-containing proteins, and complemented Cth2 deletion in yeast, thus establishing TTP as the functional homolog of Cth2 in mammalian iron regulation. Finally, TTP levels were increased by rapamycin in IRP1/2-independent manner, and genetic knockout of TTP in MEFs significantly reversed the effects of rapamycin on TfR1 mRNA levels and stability. These findings establish TTP as the mediator of iron-regulatory effects of mTOR and provide a novel link between energy metabolism, inflammation and iron regulatory pathways. Conclusions: We identified a novel pathway of cellular iron regulation by mTOR and TTP, which complements the “classical” IRP1/2 model.

scholarly journals Interferon-α induces nitric oxide synthase expression and haem oxygenase-1 down-regulation in microglia: implications of cellular mechanism of IFN-α-induced depression

2012 ◽  
Vol 16 (2) ◽  
pp. 433-444 ◽  
Author(s):  
Dah-Yuu Lu ◽  
Yuk-Man Leung ◽  
Kuan-Pin Su
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Animal Studies ◽  
Janus Kinase ◽  
Interferon Α ◽  
Signal Pathways ◽  
Cellular Mechanisms ◽  
Down Regulation ◽  
Haem Oxygenase ◽  
Oxide Synthase

Abstract Substantiating evidence for the inflammation theory of depression is that interferon-alpha (IFN-α) induces clinical depression. Despite numerous researches on neurochemical and neuroendocrinological mechanisms from human and animal studies, the direct mechanisms of IFN-α at cellular levels are still lacking. In this study, we aimed to identify the cellular mechanisms for IFN-α-induced neuroinflammatory response with the murine BV-2 microglia cell line. IFN-α potently induced nitric oxide synthase (iNOS) and nitric oxide (NO) release and down-regulated haem oxygenase-1 (HO-1) expression, which could be dampened by Janus kinase 1 (JAK1) and c-Jun NH2-terminal kinase (JNK) inhibition, respectively. IFN-α activated JAK1, JNK, signal transducers and activators of transcription (STAT)1 and STAT3, but not extracellular signal-regulated kinases (ERK) and phosphoinositide 3 (PI3) kinase, signal pathways. The transfection with STAT1 and STAT3 siRNA also inhibited IFN-α-induced iNOS/NO expression and HO-1 down-regulation. The HO-1 activator, CoppIX, reversed iNOS/NO up-regulation and HO-1 down-regulation induced by IFN-α. On the other hand, a knockdown of HO-1 expression enhanced IFN-α-induced iNOS/NO expression. The effects of IFN-α-induced iNOS/NO up-regulation and HO-1 down-regulation in microglia are associated with JAK1/JNK/STAT1 and STAT3 signalling pathways. The different effects between IFN-α and IFN-γ on HO-1 regulation and ERK phosphorylation might provide a possible explanation of different risk in their induction of neuropsychiatric adverse effects in clinical and animal studies. The results from this study add the missing part of direct cellular mechanisms for IFN-α-induced depression.

scholarly journals Iron Deficiency as a Therapeutic Target in Cardiovascular Disease

2019 ◽  
Vol 12 (3) ◽  
pp. 125 ◽  
Author(s):  
Samira Lakhal-Littleton
Keyword(s):  
Heart Failure ◽  
Cardiovascular Disease ◽  
Cardiovascular Diseases ◽  
Chronic Heart Failure ◽  
Iron Deficiency ◽  
Iron Supplementation ◽  
Iron Homeostasis ◽  
Iron Regulatory Proteins ◽  
Cellular Iron ◽  
Cellular Iron Homeostasis

Iron deficiency is the most common nutritional disorder in the world. It is prevalent amongst patients with cardiovascular disease, in whom it is associated with worse clinical outcomes. The benefits of iron supplementation have been established in chronic heart failure, but data on their effectiveness in other cardiovascular diseases are lacking or conflicting. Realising the potential of iron therapies in cardiovascular disease requires understanding of the mechanisms through which iron deficiency affects cardiovascular function, and the cell types in which such mechanisms operate. That understanding has been enhanced by recent insights into the roles of hepcidin and iron regulatory proteins (IRPs) in cellular iron homeostasis within cardiovascular cells. These studies identify intracellular iron deficiency within the cardiovascular tissue as an important contributor to the disease process, and present novel therapeutic strategies based on targeting the machinery of cellular iron homeostasis rather than direct iron supplementation. This review discusses these new insights and their wider implications for the treatment of cardiovascular diseases, focusing on two disease conditions: chronic heart failure and pulmonary arterial hypertension.

IL-1 inhibits beta-adrenergic control of cardiac calcium current: role of L-arginine/nitric oxide pathway

1994 ◽  
Vol 267 (5) ◽  
pp. H1753-H1758 ◽  
Author(s):  
G. J. Rozanski ◽  
R. C. Witt
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Ventricular Myocytes ◽  
Interleukin 1 ◽  
Cell Voltage ◽  
Cellular Mechanisms ◽  
Beta Adrenergic ◽  
Nitric Oxide Synthase Inhibitor ◽  
Adrenergic Control ◽  
Oxide Synthase

Modulation of the beta-adrenergic control of cardiac L-type Ca2+ current (Ica) by human recombinant interleukin-1 beta (IL-1) was examined in adult guinea pig ventricular myocytes using the whole cell voltage-clamp technique. ICa was elicited in Cs(+)-loaded myocytes by depolarizing pulses from a holding potential of -40 mV. Isoproterenol (0.01 and 1 microM) exposed to myocytes pretreated with 1 ng/ml IL-1 evoked a significantly smaller increase in ICa density compared with control cells. This IL-1-mediated decrease in beta-responsiveness was usually observed with pretreatment periods of > 1 h and varied as a function of the L-arginine concentration of the pretreatment medium. In addition, it was prevented by 1) IL-1 receptor antagonist, 2) substituting D-arginine for L-arginine, or 3) incubating cells with the nitric oxide synthase inhibitor NG-monomethyl-L-arginine. Thus the present data illustrate that IL-1 significantly alters the beta-adrenergic control of cardiac Ca2+ channels by cellular mechanisms that involve the activation of nitric oxide synthase. These mechanisms may play a role in altering ventricular function during cytokine-mediated inflammatory processes affecting the heart.

XPS and UPS study of the reaction of carbon monoxide with oxygen and nitrogen monoxide on platinum-rhenium alloy

1982 ◽  
Vol 114 (2-3) ◽  
pp. L48-L56
Author(s):  
M. Alnot ◽  
A. Cassuto ◽  
R. Ducros ◽  
J.J. Ehrhardt ◽  
B. Weber
Keyword(s):  
Carbon Monoxide ◽  
Nitrogen Monoxide ◽  
Rhenium Alloy
Sign in / Sign up

Export Citation Format

Share Document