Dietary iron deficiency induces ventricular dilation, mitochondrial ultrastructural aberrations and cytochrome c release: involvement of nitric oxide synthase and protein tyrosine nitration

2005 ◽  
Vol 109 (3) ◽  
pp. 277-286 ◽  
Author(s):  
Feng Dong ◽  
Xiaochun Zhang ◽  
Bruce Culver ◽  
Herbert G. Chew ◽  
Robert O. Kelley ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Cytochrome C ◽  
Nadph Oxidase ◽  
Dietary Iron ◽  
Cytochrome C Release ◽  
Caveolin 1 ◽  
Iron Deficient ◽  
Oxide Synthase ◽  
Cardiac Ultrastructure ◽  
Deficient Group

Iron deficiency is associated with multiple health problems, including the cardiovascular system. However, the mechanism of action of iron-deficiency-induced cardiovascular damage is unclear. The aim of the present study was to examine the effect of dietary iron deficiency on cardiac ultrastructure, mitochondrial cytochrome c release, NOS (nitric oxide synthase) and several stress-related protein molecules, including protein nitrotyrosine, the p47phox subunit of NADPH oxidase, caveolin-1 and RhoA. Male weanling rats were fed with either control or iron-deficient diets for 12 weeks. Cardiac ultrastructure was examined by transmission electron microscopy. Western blot analysis was used to evaluate cytochrome c, endothelial and inducible NOS, NADPH oxidase, caveolin-1 and RhoA. Protein nitrotyrosine formation was measured by ELISA. Rats fed an iron-deficient diet exhibited increased heart weight and size compared with the control group. Heart width, length and ventricular free wall thickness were similar between the two groups. However, the left ventricular dimension and chamber volume were significantly enhanced in the iron-deficient group compared with controls. Ultrastructural examination revealed mitochondrial swelling and abnormal sarcomere structure in iron-deficient ventricular tissues. Cytochrome c release was significantly enhanced in iron-deficient rats. Protein expression of eNOS (endothelial NOS) and iNOS (inducible NOS), and protein nitrotyrosine formation were significantly elevated in cardiac tissue or mitochondrial extraction from the iron-deficient group. Significantly up-regulated NADPH oxidase, caveolin-1 and RhoA expression were also detected in ventricular tissue of the iron-deficient group. Taken together, these results suggest that dietary iron deficiency may have induced cardiac hypertrophy characterized by aberrant mitochondrial and irregular sarcomere organization, which was accompanied by increased reactive nitrogen species and RhoA expression.

Developmental iron deficiency dysregulates TET activity and DNA hydroxymethylation in the rat hippocampus and cerebellum

2022 ◽  
Author(s):  
Amanda K. Barks ◽  
Montana M. Beeson ◽  
Timothy C. Hallstrom ◽  
Michael K. Georgieff ◽  
Phu V. Tran
Keyword(s):  
Iron Deficiency ◽  
Neural Circuit ◽  
Epigenetic Modification ◽  
Rat Hippocampus ◽  
Dietary Iron ◽  
Deficient Diet ◽  
Dna Hydroxymethylation ◽  
Iron Treatment ◽  
Iron Deficient ◽  
Increased Risk

Iron deficiency (ID) during neurodevelopment is associated with lasting cognitive and socioemotional deficits, and increased risk for neuropsychiatric disease throughout the lifespan. These neurophenotypical changes are underlain by gene dysregulation in the brain that outlasts the period of ID; however, the mechanisms by which ID establishes and maintains gene expression changes are incompletely understood. The epigenetic modification 5-hydroxymethylcytosine (5hmC), or DNA hydroxymethylation, is one candidate mechanism because of its dependence on iron-containing TET enzymes. The aim of the present study was to determine the effect of fetal-neonatal ID on regional brain TET activity, Tet expression, and 5hmC in the developing rat hippocampus and cerebellum, and to determine whether changes are reversible with dietary iron treatment. Timed pregnant Sprague-Dawley rats were fed iron deficient diet (ID; 4 mg/kg Fe) from gestational day (G)2 to generate iron deficient anemic (IDA) offspring. Control dams were fed iron sufficient diet (IS; 200 mg/kg Fe). At postnatal day (P)7, a subset of ID-fed litters was randomized to IS diet, generating treated IDA (TIDA) offspring. At P15, hippocampus and cerebellum were isolated for subsequent analysis. TET activity was quantified by ELISA from nuclear proteins. Expression of Tet1, Tet2, and Tet3 was quantified by qPCR from total RNA. Global %5hmC was quantified by ELISA from genomic DNA. ID increased DNA hydroxymethylation (p=0.0105), with a corresponding increase in TET activity (p<0.0001) and Tet3 expression (p<0.0001) in the P15 hippocampus. In contrast, ID reduced TET activity (p=0.0016) in the P15 cerebellum, with minimal effect on DNA hydroxymethylation. Neonatal dietary iron treatment resulted in partial normalization of these changes in both brain regions. These results demonstrate that the TET/DNA hydroxymethylation system is disrupted by developmental ID in a brain region-specific manner. Differential regional disruption of this epigenetic system may contribute to the lasting neural circuit dysfunction and neurobehavioral dysfunction associated with developmental ID.

Identification of differentially expressed genes in response to dietary iron deprivation in rat duodenum

2005 ◽  
Vol 288 (5) ◽  
pp. G964-G971 ◽  
Author(s):  
James F. Collins ◽  
Christina A. Franck ◽  
Kris V. Kowdley ◽  
Fayez K. Ghishan
Keyword(s):  
Iron Deficiency ◽  
Real Time ◽  
Real Time Pcr ◽  
Iron Transport ◽  
Dietary Iron ◽  
Cancer Resistance ◽  
Novel Genes ◽  
Copper Absorption ◽  
Iron Deprivation ◽  
Iron Deficient

We sought to identify novel genes involved in intestinal iron absorption by inducing iron deficiency in rats during postnatal development from the suckling period through adulthood. We then performed comparative gene chip analyses (RAE230A and RAE230B chips; Affymetrix) with cRNA derived from duodenal mucosa. Real-time PCR was used to confirm changes in gene expression. Genes encoding the apical iron transport-related proteins [ divalent metal transporter 1 (DMT1) and duodenal cytochrome b] were strongly induced at all ages studied, whereas increases in mRNA encoding the basolateral proteins iron-regulated gene 1 and hephaestin were observed only by real-time PCR. In addition, transferrin receptor 1 and heme oxygenase 1 were induced. We also identified induction of novel genes not previously associated with intestinal iron transport. The Menkes copper ATPase (ATP7a) and metallothionein were strongly induced at all ages studied, suggesting increased copper absorption by enterocytes during iron deficiency. We also found significantly increased liver copper levels in 7- to 12-wk-old iron-deficient rats. Also upregulated at most ages examined were the sodium-dependent vitamin C transporter, tripartite motif protein 27, aquaporin 4, lipocalin-interacting membrane receptor, and the breast cancer-resistance protein (ABCG2). Some genes also showed decreased expression with iron deprivation, including several membrane transporters, metabolic enzymes, and genes involved in the oxidative stress response. We speculate that dietary iron deprivation leads to increased intestinal copper absorption via DMT1 on the brush-border membrane and the Menkes copper ATPase on the basolateral membrane. These findings may thus explain copper loading in the iron-deficient state. We also demonstrate that many other novel genes may be differentially regulated in the setting of iron deprivation.

The Mask Mutation Identifies TMPRSS6 as an Essential Suppressor of Hepcidin Gene Expression, Required for Normal Uptake of Dietary Iron.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3-3 ◽  
Author(s):  
Ernest Beutler ◽  
Pauline Lee ◽  
Terri Gelbart ◽  
Xin Du ◽  
Bruce Beutler
Keyword(s):  
Iron Deficiency ◽  
Serine Protease ◽  
Positional Cloning ◽  
Negative Regulator ◽  
Mrna Levels ◽  
Dietary Iron ◽  
Iron Deficient ◽  
Total Body ◽  
Hepcidin Gene ◽  
Hepcidin Mrna

Abstract Hepcidin, the central negative regulator of iron absorption and iron release from macrophages, is upregulated by iron. Mutations in hemojuvelin, Hfe, transferrin receptor 2, and SMAD4 are known to prevent upregulation. Additionally, the bone morphogenetic proteins (BMPs), and the inflammatory cytokines IL-1 and IL-6 stimulate hepcidin gene activation. Downregulation of hepcidin is effected by anemia and hypoxia, but nothing is known of the mechanism through which this occurs. Here we describe the recessive ENU-induced phenotype Mask, so called because affected homozygotes developed regional alopecia in which truncal hair was shed while facial hair was retained. The Mask phenotype was found to be a manifestation of iron deficiency, and was eliminated by correcting the iron deficiency. When fed an iron deficient diet, mutant mice absorbed less iron than controls, as measured by total body 59Fe counting. After reaching a plateau total body counts stabilized, indicating that blood loss did not play a role in the iron deficiency. The level of liver hepcidin mRNA of iron deficient mice is normally greatly decreased; in contrast, the Mask mouse had high liver hepcidin mRNA levels. By positional cloning, we were able to ascribe the Mask phenotype to a splicing error in the Tmprss6 gene, which encodes a membrane-bound serine protease of previously unknown function. The mutation truncates the protein, eliminating the serine protease domain. Transfecting HepG2 cells to express the wildtype TMPRSS6 protein decreased baseline hepcidin reporter activity and almost entirely blunted the hepcidin inducing effect of IL-6, IL-1, hemojuvelin, and the BMPs. A construct encoding the Mask truncation mutant had diminished activity. Thus, TMPRSS6 powerfully down-regulates hepcidin gene transcription in the baseline state and prevents its upregulation by all known stimulators. TMPRSS6 is a non-redundant component of a hepcidin suppression pathway that exerts dominant effect over all known hepcidin inducing pathways, and is required for normal absorption of dietary iron.

Intracardiac iron distribution in newborn guinea pigs following isolated and combined fetal hypoxemia and fetal iron deficiency

1998 ◽  
Vol 76 (9) ◽  
pp. 930-936 ◽  
Author(s):  
Sixto F Gulang III ◽  
Jennifer R Merchant ◽  
Mary A Eaton ◽  
Kelly B Fandel ◽  
Michael K Georgieff
Keyword(s):  
Iron Deficiency ◽  
Cytochrome C ◽  
Guinea Pigs ◽  
Tissue Oxygenation ◽  
Myocardial Tissue ◽  
Fetal Life ◽  
Myocardial Iron ◽  
Fetal Hypoxia ◽  
Iron Deficient ◽  
Hypoxic Group

Myocardial iron deficiency complicates chronic intrauterine hypoxemia during diabetic pregnancies. To understand the effect of both conditions during fetal life on intracardiac iron prioritization, we measured heart myoglobin, cytochrome c, and elemental iron concentrations in six iron-deficient, hypoxic, five iron-sufficient, hypoxic, six iron-deficient, normoxic, and six iron-sufficient, normoxic newborn guinea pigs. The iron-deficient, hypoxic group had lower heart iron (p = 0.03) but higher myoglobin concentration (p < 0.0001) when compared with the iron-sufficient, normoxic group. The percentage of iron incorporated into myoglobin was higher than control in the iron-deficient, hypoxic group (23.2 ± 7.2% vs. 5.2 ± 0.8%; p < 0.001) and increased as total heart iron decreased (r = 0.97; p < 0.001). In contrast, heart cytochrome c concentration was lower than control in the iron-deficient, hypoxic group (p = 0.01), with equal percentages of heart iron incorporated into cytochrome c. This intracellular prioritization of myocardial iron to myoglobin and away from cytochrome c following combined fetal hypoxemia and iron deficiency may represent an adaptive mechanism to preserve myocardial tissue oxygenation, although at the expense of oxidative phosphorylative capability.Key words: fetal, hypoxia, iron deficiency, myoglobin, cytochrome c, heart.

scholarly journals An Analysis of the Etiology of Anemia and Iron Deficiency in Young Women of Low Socioeconomic Status in Bangalore, India

2007 ◽  
Vol 28 (3) ◽  
pp. 328-336 ◽  
Author(s):  
Prashanth Thankachan ◽  
Sumithra Muthayya ◽  
Thomas Walczyk ◽  
Anura V. Kurpad ◽  
Richard F. Hurrell
Keyword(s):  
Socioeconomic Status ◽  
Iron Deficiency ◽  
Dietary Intake ◽  
Serum Ferritin ◽  
Young Women ◽  
Low Socioeconomic Status ◽  
Dietary Iron ◽  
Low Socioeconomic ◽  
Blood Hemoglobin ◽  
Iron Deficient

Background Anemia and iron deficiency are significant public health problems in India, particularly among women and children. Recent figures suggest that nearly 50% of young Indian women are anemic. Objectives Few studies have comprehensively assessed etiologic factors contributing to anemia and iron deficiency in India. Hence, this study assessed the relative importance of various factors contributing to these problems in young women of low socioeconomic status in Bangalore, India. Methods A random sample of 100 nonpregnant, nonlactating women 18 to 35 years of age, selected from among 511 women living in a poor urban settlement, participated in this study. Data were obtained on demography, socioeconomic status, anthropometry, three-day dietary intake, blood hemoglobin, hemoglobinopathies, serum ferritin, serum C-reactive protein, and stool parasites. Results The prevalence rates of anemia and iron deficiency were 39% and 62%, respectively; 95% of the anemic women were iron deficient. The mean dietary iron intake was 9.5 mg per day, predominantly from the consumption of cereals, pulses, and vegetables (77%). The estimated bioavailability of nonheme iron in this diet was 2.8%. Dietary intakes were suboptimal for several nutrients. Blood hemoglobin was significantly correlated with dietary intake of fat, riboflavin, milk and yogurt, and coffee. Serum ferritin was significantly correlated with intake of niacin, vitamin B12, and selenium. Parasitic infestation was low. Conclusions An inadequate intake of dietary iron, its poor bioavailability, and concurrent inadequate intake of dietary micronutrients appear to be the primary factors responsible for the high prevalence of anemia and iron deficiency in this population.

scholarly journals Ferric Carboxymaltose-Mediated Attenuation of Doxorubicin-Induced Cardiotoxicity in an Iron Deficiency Rat Model

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Jorge Eduardo Toblli ◽  
Carlos Rivas ◽  
Gabriel Cao ◽  
Jorge Fernando Giani ◽  
Felix Funk ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Nitrosative Stress ◽  
Ferric Carboxymaltose ◽  
Necrosis Factor Alpha ◽  
Spontaneously Hypertensive ◽  
Caveolin 1 ◽  
Neutrophil Gelatinase Associated Lipocalin ◽  
Stress Markers ◽  
Neutrophil Gelatinase ◽  
Oxide Synthase

Since anthracycline-induced cardiotoxicity (AIC), a complication of anthracycline-based chemotherapies, is thought to involve iron, concerns exist about using iron for anaemia treatment in anthracycline-receiving cancer patients. This study evaluated how intravenous ferric carboxymaltose (FCM) modulates the influence of iron deficiency anaemia (IDA) and doxorubicin (3–5 mg per kg body weight [BW]) on oxidative/nitrosative stress, inflammation, and cardiorenal function in spontaneously hypertensive stroke-prone (SHR-SP) rats. FCM was given as repeated small or single total dose (15 mg iron per kg BW), either concurrent with or three days after doxorubicin. IDA (after dietary iron restriction) induced cardiac and renal oxidative stress (markers included malondialdehyde, catalase, Cu,Zn-superoxide dismutase, and glutathione peroxidase), nitrosative stress (inducible nitric oxide synthase and nitrotyrosine), inflammation (tumour necrosis factor-alpha and interleukin-6), and functional/morphological abnormalities (left ventricle end-diastolic and end-systolic diameter, fractional shortening, density of cardiomyocytes and capillaries, caveolin-1 expression, creatinine clearance, and urine neutrophil gelatinase-associated lipocalin) that were aggravated by doxorubicin. Notably, iron treatment with FCM did not exacerbate but attenuated the cardiorenal effects of IDA and doxorubicin independent of the iron dosing regimen. The results of this model suggest that intravenous FCM can be used concomitantly with an anthracycline-based chemotherapy without increasing signs of AIC.

Dietary iron-deficient anemia induces a variety of metabolic changes and even apoptosis in rat liver: a DNA microarray study

2010 ◽  
Vol 42 (2) ◽  
pp. 149-156 ◽  
Author(s):  
Asuka Kamei ◽  
Yuki Watanabe ◽  
Tomoko Ishijima ◽  
Mariko Uehara ◽  
Soichi Arai ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Iron Deficiency ◽  
Dna Microarray ◽  
Global Analysis ◽  
Control Diet ◽  
Diet Group ◽  
Iron Level ◽  
Dietary Iron ◽  
Deficient Diet ◽  
Iron Deficient

Anemia can be induced by dietary iron deficiency, as well as by hemorrhagia. It may also be associated with changes in lipid metabolism. However, no global analysis detailing the consequences of iron deficiency in the liver has yet been conducted. Since the liver is a metabolically important organ and also a major iron-storing organ, we performed a comprehensive transcriptome analysis to determine the effects of iron deficiency on hepatic gene expression. Four-week-old rats were fed an iron-deficient diet, ∼3 ppm iron, ad libitum for 16 days. These rats were compared with similar rats pair-fed a control diet with a normal iron level, 48 ppm iron. The 16-day iron-deficient diet apparently induced anemia. On day 17, the rats were killed under anesthesia, and their livers were dissected for DNA microarray analysis. We identified 600 upregulated and 500 downregulated probe sets that characterized the iron-deficient diet group. In the upregulated probe sets, genes involved in cholesterol, amino acid, and glucose metabolism were significantly enriched, while genes related to lipid metabolism were significantly enriched in the downregulated probe sets. We also found that genes for caspases 3 and 12, which mediate endoplasmic reticulum (ER)-specific apoptosis, were upregulated in the iron-deficient group. Combined, these results suggest that iron deficiency exerts various influences, not only on nutrient metabolism but also on apoptosis, as a consequence of ER stress in the liver.

DISTRIBUTION OF CYTOCHROME C AND MYOGLOBIN IN RATS WITH DIETARY IRON DEFICIENCY

PEDIATRICS ◽  
1965 ◽  
Vol 35 (4) ◽  
pp. 677-686
Author(s):  
Peter R. Dallman ◽  
Herbert C. Schwartz
Keyword(s):  
Skeletal Muscle ◽  
Cytochrome C ◽  
Intestinal Mucosa ◽  
Dietary Iron ◽  
Cell Turnover ◽  
Organ Function ◽  
Diaphragmatic Muscle ◽  
Iron Deprivation ◽  
Iron Deficient ◽  
Significant Impairment

A decrease in cytochrome c and myoglobin concentrations was observed in young rats made anemic on a low-iron diet. The degree of depletion of hemeprotein varied according to tissue. In the iron-deficient rat, myoglobin and cytochrome c were most depleted in skeletal muscle which contains the major portion of these proteins. Cytochrome c expressed as percentage of corresponding control mean concentrations was 44% in skeletal muscle, 61% in intestinal mucosa, 69% in kidney, 79% in diaphragm, 89% in heart, and 97% in brain. Myoglobin in the iron-deficient rats was 44% of the corresponding control concentration in skeletal muscle, 63% in diaphragmatic muscle, and 80% in heart muscle. The variations in degree of hemeprotein depletion in response to iron deprivation appeared to be related to organ function, growth rate, and cell turnover. Cardiac and diaphragmatic muscle, whose function is essential to survival, resisted the loss of myoglobin and cytochrome c to a greater extent than did skeletal muscle. Severe depletion of hemeprotein was observed in tissues with a rapid rate of growth such as skeletal muscle or a rapid cell turnover as in the case of intestinal mucosa. Brain, which grows minimally during the period of iron deprivation, was unchanged in its cytochrome c content. A significant impairment of oxidative metabolism in the iron deficient rat was suggested by a reduction in the rate of respiration of muscle homogenates.

scholarly journals Release of Mitochondrial Apoptogenic Factors and Cell Death are Mediated by CK2 and NADPH Oxidase

2011 ◽  
Vol 32 (4) ◽  
pp. 720-730 ◽  
Author(s):  
Gab Seok Kim ◽  
Joo Eun Jung ◽  
Purnima Narasimhan ◽  
Hiroyuki Sakata ◽  
Hideyuki Yoshioka ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cytochrome C ◽  
Nadph Oxidase ◽  
Ischemia Reperfusion ◽  
Brain Infarction ◽  
Ischemic Injury ◽  
Artery Occlusion ◽  
Cytochrome C Release ◽  
Copper Zinc Superoxide Dismutase ◽  
Cerebral Ischemia And Reperfusion

Activation of the NADPH oxidase subunit, NOX2, and increased oxidative stress are associated with neuronal death after cerebral ischemia and reperfusion. Inhibition of NOX2 by casein kinase 2 (CK2) leads to neuronal survival, but the mechanism is unknown. In this study, we show that in copper/zinc-superoxide dismutase transgenic (SOD1 Tg) mice, degradation of CK2α and CK2α′ and dephosphorylation of CK2β against oxidative stress were markedly reduced compared with wild-type (WT) mice that underwent middle cerebral artery occlusion. Inhibition of CK2 pharmacologically or by ischemic reperfusion facilitated accumulation of poly(ADP-ribose) polymers, the translocation of apoptosis-inducing factor (AIF), and cytochrome c release from mitochondria after ischemic injury. The eventual enhancement of CK2 inhibition under ischemic injury strongly increased 8-hydroxy-2′-deoxyguanosine and phosphorylation of H2A.X. Furthermore, CK2 inhibition by tetrabromocinnamic acid (TBCA) in SOD1 Tg and gp91 knockout (KO) mice after ischemia reperfusion induced less release of AIF and cytochrome c than in TBCA-treated WT mice. Inhibition of CK2 in gp91 KO mice subjected to ischemia reperfusion did not increase brain infarction compared with TBCA-treated WT mice. These results strongly suggest that NOX2 activation releases reactive oxygen species after CK2 inhibition, triggering release of apoptogenic factors from mitochondria and inducing DNA damage after ischemic brain injury.

Effects of iron deficiency and training on mitochondrial enzymes in skeletal muscle

1987 ◽  
Vol 62 (6) ◽  
pp. 2442-2446 ◽  
Author(s):  
W. T. Willis ◽  
G. A. Brooks ◽  
S. A. Henderson ◽  
P. R. Dallman
Keyword(s):  
Skeletal Muscle ◽  
Iron Deficiency ◽  
Cytochrome C ◽  
Endurance Training ◽  
Tricarboxylic Acid Cycle ◽  
Interactive Effect ◽  
Tricarboxylic Acid ◽  
Mitochondrial Enzymes ◽  
Acid Cycle ◽  
Iron Deficient

We measured mitochondrial enzyme activities in skeletal muscle under conditions of iron deficiency and endurance training to assess the effects of these interventions on the contents and proportions of non-iron-containing and iron-dependent enzymes and proteins. Male Sprague-Dawley rats, 21 days of age, received a diet containing either 6 (iron deficient) or 50 mg iron/kg diet (iron sufficient). At 35 days of age animals were subdivided into sedentary and endurance training groups (running at 0.7 mph, 0% grade, 45 min/day, 6 days/wk). By 70 days of age, iron deficiency had decreased gastrocnemius muscle cytochrome c by 62% in sedentary animals. In contrast, the activities of tricarboxylic acid cycle enzymes were increased, remained unchanged or were slightly decreased, indicating that iron deficiency markedly altered mitochondrial composition. Endurance training increased cytochrome c (35%), tricarboxylic acid cycle enzymes (approximately 15%), and manganese superoxide dismutase (33%) in iron-deficient rats, whereas the same exercise regimen had no effect on the skeletal muscle of iron-sufficient animals. The interactive effect of dietary iron deficiency and mild exercise on mitochondrial enzymes suggests that adaptation to a training stimulus is, to some extent, geared to the relationship between the energy demand of exercise and the capacity for O2 transport and utilization.

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