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Endocrinology Vol. 148, No. 6 2663-2668
Copyright © 2007 by The Endocrine Society

The Iron Regulatory Peptide Hepcidin Is Expressed in the Heart and Regulated by Hypoxia and Inflammation

Uta Merle, Evelyn Fein, Sven Gustav Gehrke, Wolfgang Stremmel and Hasan Kulaksiz

Department of Internal Medicine IV, University Hospital of Heidelberg, D-69120 Heidelberg, Germany

Address all correspondence and requests for reprints to: Dr. Hasan Kulaksiz, University Hospital Heidelberg, Department of Internal Medicine IV, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. E-mail: hasan_kulaksiz{at}med.uni-heidelberg.de.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The peptide hormone hepcidin plays a central role in iron homeostasis. It is predominantly expressed in the liver and regulated by iron, hypoxia, and inflammation. Although it has been shown that iron plays a key pathophysiological role in cardiac diseases, including iron-overload cardiomyopathy, myocardial ischemia-reperfusion injury, and atherosclerosis, very little is known about the putative expression and the role of hepcidin in the heart. In the present study, expression and regulation of hepcidin in rat heart were analyzed. Basal cardiac expression of hepcidin was demonstrated on mRNA and protein level in vivo in a rat model and compared with its regulation in the liver. The cellular localization was analyzed by immunofluorescence microscopy. Sixteen hours after a single injection of turpentine, a more than 2-fold increase of cardiac hepcidin mRNA and a more than 3-fold increase of hepatic hepcidin mRNA was observed. In response to hypoxia, expression of hepcidin in the liver decreased. In contrast, hypoxia resulted in a strong up-regulation of hepcidin expression on mRNA and protein level in the heart, accompanied by an increased immunoreactivity of hepcidin pronounced at the myocardial intercalated disc area. The finding of a regulated expression of the iron-regulatory peptide hormone hepcidin in the heart suggests that hepcidin may have an important role in cardiac diseases.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
IRON IS ESSENTIAL for a variety of metabolic processes but may also cause potentially deleterious effects. It plays a key pathophysiological role in cardiac diseases as seen in iron-overload cardiomyopathy (1, 2), myocardial ischemia-reperfusion injury (3, 4), and atherosclerosis (5, 6). Myocardial ischemia results in an enhanced ferritin content in relation to the degree of ischemia (7, 8, 9). However, the mechanism(s) by which myocardial iron content is regulated is unclear.

The recently discovered peptide hormone hepcidin is primarily expressed in the liver and represents a central regulator of iron homeostasis (10, 11). Mutations in the hepcidin gene are associated with juvenile hemochromatosis (12). Under physiological conditions, hepcidin negatively regulates iron absorption in the duodenum and iron transport in reticuloendothelial cells by binding to the iron exporter ferroportin. By binding to ferroportin at the basolateral membrane of duodenal enterocytes and at macrophages, hepcidin causes the internalization of ferroportin, resulting in an inhibition of iron transport (13). In addition to the capacity of hepcidin to inhibit iron release by interaction with ferroportin, physiologically generated hepcidin results in a concomitant de-repression of ferritin synthesis (14).

The hepatic expression of hepcidin is down-regulated in response to low body iron stores, anemia, and hypoxia (10). Conversely, hepcidin expression is induced by iron overload (11) and by inflammatory signals (13, 15). Although the majority of studies focused on the function and regulation of hepcidin in the liver as the major site of hepcidin production, accumulating data suggest that this bioactive peptide may also play a role in other tissues.

Because of the key pathophysiological role of iron in cardiac diseases, the iron-regulatory peptide hormone hepcidin may be central in cardiac diseases, too. We thus investigated expression, cellular localization, and regulation of myocardial hepcidin under hypoxia and inflammation.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
Male Sprague Dawley rats (200–250 g) were purchased from Charles River Laboratories (Sulzfeld, Germany) and housed in the central animal facility of the University of Heidelberg with a 12-h light, 12-h dark cycle. All animals used in this study received a standard rodent chow (M-Z Ereich, 176 mg/kg iron content; Ssniff, Soest, Germany) and water ad libitum. Animal studies were in compliance with the guidelines of the Institutional Animal Care and with the Guide for the Care and Use of Laboratory Animals published by the United States National Institutes of Health (Publication 85-23, revised 1996).

Induction of acute-phase inflammation
Male Sprague Dawley rats received a single sc injection of turpentine oil (50 µl/100 g body weight; Sigma-Aldrich, Taufkirchen, Germany) into the interscapular fat pad and were killed after 16 h for analysis. Control rats were similarly injected with an equal volume of saline.

In vivo hypoxia
Male Sprague Dawley rats were exposed to hypoxia [8 and 6% O2 in an N2/O2 (vol/vol) gas mix] in an acrylic box (160-liter volume), with food and water ad libitum, and killed after 24 h or 5 d of hypoxia for analysis (16). Controls remained in room air. The gas flow was adjusted to maintain 20 C and to prevent an increase in CO2 inside the box. The gas composition in the box was checked with a blood gas analyzer (model 278; Ciba-Corning, Fernwald, Germany).

Rat tissue collection
Tissue specimens from heart and liver were resected and immediately frozen in liquid nitrogen for Western blot analysis or in Tissue-Tek O.C.T. compound (Sakura Finetek, Torrance, CA) for immunofluorescence analysis. For RT-PCR analysis, tissue samples were stored at –20 C in RNAlater solution (Ambion, Austin, TX) before RNA isolation.

Quantitative RT-PCR
Total RNA was isolated from rat heart and liver samples using the RNAeasy Mini kit (Qiagen, Hilden, Germany) including deoxyribonuclease digestion according to the instructions of the manufacturer. As described previously (17, 18), real-time quantification of hepcidin and ß-actin mRNA transcripts was performed with a two-step RT-PCR using the LightCycler system and the Relative Quantification Software version 1.0 (Roche Diagnostics, Mannheim, Germany).

Quantification of rat hepcidin mRNA transcripts was performed using the sense primer (5'-GGC AGA AAG CAA GAC TGA TGA C) and the antisense primer (5'-ACA GGA ATA AAT AAT GGG GCG). Normalization to actin mRNA levels was performed as described previously using the sense primer (5'-TGA CGT TGA CAT CCG TAA AGA C) and the antisense primer (5'-CAG TGA GGC CAG GAT AGA GC) (17, 19). Normalization to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA levels was performed using the sense primer (5'-TGC CAC TCA GAA GAC TGT GG) and the antisense primer (GAT CCA CAA CGG ATA CAT TGG). Calibrators for rat hepcidin, actin, and GAPDH were generated from rat expressed sequence tag clones [IMAGE (Integrated Molecular Analysis of Genomes and their Expression Database) identification nos. 1772886 and 6920838 and GenBank accession no. BI277569, respectively; from RZPD (Deutsches Ressourcenzentrum für Genomforschung), Berlin, Germany].

Immunoblot analysis
Proteins from rat heart and liver were extracted according to the published protocols (20). Protein concentrations were determined by using the Bio-Rad (Bradford) protein assay (Bio-Rad, Hercules, CA) with BSA as a standard. Samples containing equal amounts of protein (20 µg) were subjected to immunoblot experiments, performed as described previously with the primary hepcidin antibodies EG(1)-HepN and EG(2)-HepC (18, 21). The immunoblot membranes were scanned, and the optical density of each sample was quantified by densitometry. The band density measurements were expressed as relative density units.

Immunofluorescence analysis
Five-micrometer-thick serial cryostat sections were used. After blocking with 5% skim milk in PBS (pH 7.4) for 1 h at room temperature, sections were incubated with primary hepcidin antibodies EG(1)-HepN and EG(2)-HepC (diluted 1:1000 in PBS) overnight at 4 C, followed by incubation with cyanine 3-coupled secondary antibody (Dianova, Hamburg, Germany). Immunostaining was visualized on a Leica (Nussloch, Germany) fluorescence microscope equipped with a high-pressure mercury lamp and the appropriate filter sets. Images were acquired with a digital camera and processed with MetaVue software (Universal Imaging via Visitron, Puchheim, Germany). Hepcidin antibody was produced and characterized previously (18, 20, 21, 22, 23).

Specificity controls
Method-dependent nonspecificities were excluded by running controls as described previously (18, 20). Antibody specificities were tested by preadsorption of the hepcidin antibody with homologous antigens (6.25 µg/ml). Preadsorption with heterologous antigens (100 µg/ml) had no effect on immunostaining.

Statistical analysis
Statistical analysis of quantitative variables was performed using the nonparametric Mann-Whitney test. A P value less than 0.05 was considered significant. All statistical analyses were performed using SPSS version 11.0.1 (SPSS, Chicago, IL).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Expression of hepcidin in the rat myocardium
The cardiac expression of hepcidin mRNA was studied by quantitative real-time RT-PCR analysis and revealed a clear expression of the expected 201 bp product of hepcidin in rat heart (Fig. 1Go).


Figure 1
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  		FIG. 1. A, RT-PCR analyses of rat liver (lane 2) and heart (lane 3) hepcidin expression with an expected 201-bp PCR product. A base pair ladder is indicated (lane 1). B, Immunoblot analysis of hepcidin in extracts of rat heart (normoxia and 6% oxygen) with N-terminal antibody EG(1 )-HepN. Note the immunoreactive bands at 9.5 kDa obtained for rat heart. Immunoreactivity is analyzed by densitometric quantification of the individual bands and is stronger in extracts of heart of a rat housed 24 h under hypoxia (6% oxygen) than under normoxia. Quantification by densitometry revealed a relative band density of rat heart under normoxia of 38% compared with hypoxia.

 
At the translational level, the presence of hepcidin was confirmed by immunoblot and immunofluorescence analyses with region-specific hepcidin antibodies. Immunoblot studies with antibodies directed against N- and C-terminus of the hepcidin precursor molecule identified an immunoreactive band of approximately 9.5 kDa in extracts of rat heart (Fig. 1Go). By immunofluorescence analysis, hepcidin immunoreactivity was localized in cardiomyocytes pronounced at the intercalated disc region (Fig. 2Go). Under hypoxia, hepcidin expression increased clearly at the intercalated disc region (Fig. 2Go).


Figure 2
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  		FIG. 2. Cellular localization of immunoreactive hepcidin in cryosections of the left ventricle of rat heart using the hepcidin antibody EG(2 )-HepC. A, Normoxic rat, x400. B, Normoxic rat after preadsorption of the antibody with hepcidin peptide immunogen, x200. C, Hypoxic rat (6% oxygen), x200. D, Hypoxic rat (6% oxygen), x400. E and F, Hypoxic rat (6% oxygen), x600. Note the strong immunostaining at the intercalated disc region (arrowheads), which is increased under hypoxia.

 
Cardiac and hepatic hepcidin gene expressions are tightly controlled by hypoxia
Expression of hepcidin in rat liver and heart was analyzed after 1 and 5 d of different levels of hypoxia (8 and 6% of oxygen). Quantitative real-time RT-PCR was performed with actin and GAPDH as internal standards. When compared with normoxic controls, hepatic hepcidin gene expression was strongly downregulated by acute (1 d) and chronic (5 d) hypoxia (Figs. 3Go and 4Go). Both tested levels of hypoxia, 8 and 6% of oxygen, resulted in a significantly lower expression level of hepcidin when compared with controls. There was no significant difference in hepatic hepcidin expression when comparing hypoxia with 8 and 6% oxygen (Fig. 3Go).


Figure 3
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  		FIG. 3. Quantitative RT-PCR analysis of hepcidin (Hamp) expression in rat liver (A and B) and heart (C and D) tissue homogenates. Rats were housed under different levels of oxygen (normoxic, 8% oxygen, and 6% oxygen) for 24 h. The expression levels of hepcidin are given as the amount relative to the expression of the housekeeping genes actin (A and C) and GAPDH (B and D) in each sample. Bars indicate means (n = 6), and error bars indicate SD. Note the controversial regulation of hepcidin in heart and liver.

 

Figure 4
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  		FIG. 4. Quantitative RT-PCR analysis of hepcidin (Hamp) expression in rat liver (A and B) and heart (C and D) tissue homogenates. Rats were housed under hypoxia (8% oxygen) and normoxic conditions for 5 d. The expression levels of hepcidin are given as the amount relative to the expression of the housekeeping genes actin (A and C) and GAPDH (B and D) in each sample. Bars indicate means (n = 6), and error bars indicate SD. Note the controversial regulation of hepcidin in heart and liver.

 
In contrast, cardiac hepcidin expression was increased in rats exposed to acute (1 d) and chronic (5 d) hypoxia compared with normoxic controls (Figs. 3Go and 4Go). The increase of hepcidin mRNA expression after 1 d of hypoxia was dose dependent. Under hypoxic conditions with 8% O2, hepcidin mRNA increased approximately 3-fold compared with normoxic controls, whereas under hypoxic conditions with 6% O2, hepcidin mRNA was upregulated approximately 15-fold compared with normoxic controls (Fig. 3Go). Up-regulation of cardiac hepcidin mRNA was paralleled by an increase at protein level (Fig. 1Go). Quantification by densitometry revealed an approximately 3-fold higher expression level of hepcidin in hypoxic rat heart compared with normoxic control rat heart (Fig. 1Go). This was accompanied by a stronger cellular immunoreactivity of hepcidin in hypoxic rat heart, pronounced at the myocardial intercalated disc area (Fig. 2Go).

Cardiac and hepatic hepcidin gene expressions are regulated by inflammation
Sixteen hours after a single injection of turpentine, a significant increase in hepcidin gene expression was observed in the heart as well as the liver (Fig. 5Go). This was true for quantification of mRNA with actin as well as GAPDH as internal standard.


Figure 5
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  		FIG. 5. Quantitative RT-PCR analysis of hepcidin (Hamp) expression in rat liver (A and B) and heart (C and D) tissue homogenates. Rats were injected with turpentine for induction of inflammation or injected with normal saline (control). The expression levels of hepcidin are given as the amount relative to the expression of the housekeeping genes actin (A and C) and GAPDH (B and D) in each sample. Bars indicate means (n = 10), and error bars indicate SD.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Elevated cardiac iron is associated with cardiac diseases such as diastolic dysfunction, arrhythmia, and dilated cardiomyopathy (24). Moreover, cardiac ischemia can result in an increase in cardiac ferritin content related to the degree of ischemia (7, 8, 9). Despite these clear connections between elevated cardiac iron content and cardiac diseases (24), the regulation of cardiac iron metabolism remains poorly understood. Thus, we studied the expression of the iron regulatory peptide hormone hepcidin and its regulation in the heart.

Quantitative real-time RT-PCR analysis clearly revealed that hepcidin is not only expressed on mRNA level in rat liver but also in rat heart. To analyze the presence of hepcidin on protein level, we performed immunoblot and immunofluorescence analyses. Immunoblot and immunofluorescence analysis with previously characterized, specific hepcidin antibodies showed expression of hepcidin at protein level in rat heart. Immunofluorescence analysis revealed hepcidin immunoreactivity in cardiomyocytes pronounced at the intercalated disc region.

Because hepatic hepcidin expression is regulated by hypoxia and inflammation, factors influencing iron homeostasis (10), we analyzed whether cardiac hepcidin expression is regulated in response to these stimuli, too. In our study, we could demonstrate clearly that cardiac hepcidin expression is regulated in response to hypoxia and inflammation. Our data show that, in contrast to the liver, in which hypoxia results in down-regulation of hepcidin expression, cardiac hepcidin expression is significantly up-regulated in response to hypoxia. Hepcidin produced in the liver and released into the blood is supposed to have a systemic effect by negatively regulating iron absorption in the duodenum. The down-regulation of hepatic hepcidin expression in response to hypoxia and anemia results in increased intestinal iron absorption (10). Cardiac hepcidin expression may have predominantly a local effect in the heart. By a proposed local effect, the observed up-regulation of cardiac hepcidin expression in response to hypoxia may explain the previously reported ischemia-related enhanced cardiac ferritin content. Ferritin is a major intracellular iron sequestering and storage protein that is assumed to play an important cytoprotective role against free radical formation by controlling the free cytosolic iron concentration (25). Because elevated hepcidin can result in an increased intracellular ferritin content (14), we speculate that the up-regulation of hepcidin in response to hypoxia may provide a coordinated mechanism for protecting cardiac cells against the hypoxia-related free radical formation by controlling the free cytosolic iron concentration.

As shown by immunofluorescence analysis, hepcidin immunoreactivity increases at the intercalated disc area of cardiomyocytes under hypoxic conditions. Because the intercalated discs have been shown recently to be relevant in a variety of cardiac diseases, especially in dilated cardiomyopathy and arrhythmia (26, 27, 28), we speculate that the presence of hepcidin at this location and its up-regulation under hypoxia may provide a kind of subcellular control of reactive iron at the intercalated disc area, which may have a particular susceptibility to iron toxicity. The presence of hepcidin at the intercalated disc area may protect against iron-mediated compromise of conduction, which is regularly observed in cardiac iron overload. However, the exact function of hepcidin at the intercalated disc area needs additional studies.

The physiological function of hepcidin in the heart may also be related to the divalent metal transporter 1 (DMT1). DMT1 is an integral membrane-bound transport protein that increases the uptake of Fe2+ and other divalent cations such as Zn2+, Cu2+, and Mn2+ in a pH-dependent manner by a proton-coupled process (29). In the proximal intestine, after its reduction, iron is transported across the brush border membrane via DMT1 (30) and released into the plasma via the basolaterally located transporter ferroportin (31). Interestingly, the iron transporter DMT1 is also expressed in the heart (29, 32). Because hepcidin regulates DMT1 expression in the intestine (33, 34), we speculate that hepcidin may also regulate iron uptake into the myocardial cells via DMT1.

For the liver, it has been demonstrated previously that hepcidin is playing a key role in the regulation of iron homeostasis during inflammatory states (10, 11). Recently, inflammation caused by turpentine injection was demonstrated to induce hepatic hepcidin expression (10). In the present study, we analyzed regulation of hepcidin expression in the heart and in the liver in response to inflammation. Interestingly, in both organs, expression of hepcidin under turpentine-induced inflammation was significantly upregulated. This is in contrast to the regulation of hepcidin in response to hypoxia, in which hepcidin is inversely regulated in the heart and liver. The observed up-regulation of hepcidin in both organs in response to inflammation may be related to its antimicrobial function. Hepcidin is known as a type II acute-phase protein (35), and, in chronic inflammatory conditions, increased hepcidin levels correlate with increased ferritin levels. Thus, induction of hepcidin under inflammation in both organs, the liver and the heart, supports its proposed role as a key mediator of anemia of inflammation (36).

The rapidity of the hepcidin response to induction of inflammation with turpentine could be related to its proposed role as an inducer of hypoferremia, which would restrict iron essential for growth of infecting microbes. The observed induction of hepcidin in the heart could be particularly valuable during the earliest phases of infection, before other components of the innate and adaptive immunity are fully mobilized (35).

In conclusion, we have demonstrated that the iron regulatory peptide hepcidin is expressed in the heart and is an intrinsic cardiac hormone. Its expression is regulated in response to hypoxia and inflammation. Induction of hepcidin production by tissue hypoxia may be an important cause of ischemia-related enhanced ferritin content and may result in a reduced iron-catalyzed oxygen radical production (7, 37). Hepcidin is an acute-phase protein that is overexpressed in the liver and the heart in response to inflammation and may be an important component in local and systemic response against infection. Future studies should focus on the pathophysiology of hepcidin expression in the heart and its role in cardiac diseases.


   Acknowledgments
 
We thank Sabine Tuma and Karin Bents for expert technical support.


   Footnotes
 
First Published Online March 15, 2007

Abbreviations: DMT1, Divalent metal transporter 1; GAPDH, glyceraldehyde-3-phosphate dehydrogenase.

Statement of responsibility: The authors had full access to the data and take responsibility for its integrity. All authors have read and agree to the manuscript as written.

This study was supported by grants from the Deutsche Forschungsgemeinschaft (to H.K., S.G.G.).

H.K. and S.G.G received grant support from the Deutsche Forschungsgemeinschaft. U.M., E.F., and W.S. have nothing to disclose.

Received September 28, 2006.

Accepted for publication March 5, 2007.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Oudit GY, Sun H, Trivieri MG, Koch SE, Dawood F, Ackerley C, Yazdanpanah M, Wilson GJ, Schwartz A, Liu PP, Backx PH 2003 L-type Ca2+ channels provide a major pathway for iron entry into cardiomyocytes in iron-overload cardiomyopathy. Nat Med 9:1187–1194[CrossRef][Medline]
  2. Oudit GY, Trivieri MG, Khaper N, Husain T, Wilson GJ, Liu P, Sole MJ, Backx PH 2004 Taurine supplementation reduces oxidative stress and improves cardiovascular function in an iron-overload murine model. Circulation 109:1877–1885[Abstract/Free Full Text]
  3. Voest EE, Vreugdenhil G, Marx JJ 1994 Iron-chelating agents in non-iron overload conditions. Ann Intern Med 120:490–499[Abstract/Free Full Text]
  4. Turoczi T, Jun L, Cordis G, Morris JE, Maulik N, Stevens RG, Das DK 2003 HFE mutation and dietary iron content interact to increase ischemia/reperfusion injury of the heart in mice. Circ Res 92:1240–1246[Abstract/Free Full Text]
  5. de Valk B, Marx JJ 1999 Iron, atherosclerosis, and ischemic heart disease. Arch Intern Med 159:1542–1548[Abstract/Free Full Text]
  6. Ramakrishna G, Rooke TW, Cooper LT 2003 Iron and peripheral arterial disease: revisiting the iron hypothesis in a different light. Vasc Med 8:203–210[Abstract/Free Full Text]
  7. Loncar R, Flesche CW, Deussen A 2004 Myocardial ferritin content is closely related to the degree of ischaemia. Acta Physiol Scand 180:21–28[CrossRef][Medline]
  8. Munro HN 1990 Iron regulation of ferritin gene expression. J Cell Biochem 44:107–115[CrossRef][Medline]
  9. Voogd A, Sluiter W, van Eijk HG, Koster JF 1992 Low molecular weight iron and the oxygen paradox in isolated rat hearts. J Clin Invest 90:2050–2055[Medline]
  10. Nicolas G, Chauvet C, Viatte L, Danan JL, Bigard X, Devaux I, Beaumont C, Kahn A, Vaulont S 2002 The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest 110:1037–1044[CrossRef][Medline]
  11. Pigeon C, Ilyin G, Courselaud B, Leroyer P, Turlin B, Brissot P, Loreal O 2001 A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem 276:7811–7819[Abstract/Free Full Text]
  12. Roetto A, Papanikolaou G, Politou M, Alberti F, Girelli D, Christakis J, Loukopoulos D, Camaschella C 2003 Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nat Genet 33:21–22[CrossRef][Medline]
  13. Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, Ganz T, Kaplan J 2004 Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306:2090–2093[Abstract/Free Full Text]
  14. Andriopoulos B, Pantopoulos K 2006 Hepcidin generated by hepatoma cells inhibits iron export from co-cultured THP1 monocytes. J Hepatol 44:1125–1131[CrossRef][Medline]
  15. Lee P, Peng H, Gelbart T, Beutler E 2004 The IL-6- and lipopolysaccharide-induced transcription of hepcidin in HFE-, transferrin receptor 2-, and ß 2-microglobulin-deficient hepatocytes. Proc Natl Acad Sci USA 101:9263–9265[Abstract/Free Full Text]
  16. Wodopia R, Ko HS, Billian J, Wiesner R, Bartsch P, Mairbaurl H 2000 Hypoxia decreases proteins involved in epithelial electrolyte transport in A549 cells and rat lung. Am J Physiol Lung Cell Mol Physiol 279:L1110–L1119
  17. Gehrke SG, Kulaksiz H, Herrmann T, Riedel HD, Bents K, Veltkamp C, Stremmel W 2003 Expression of hepcidin in hereditary hemochromatosis: evidence for a regulation in response to the serum transferrin saturation and to non-transferrin-bound iron. Blood 102:371–376[Abstract/Free Full Text]
  18. Kulaksiz H, Theilig F, Bachmann S, Gehrke SG, Rost D, Janetzko A, Cetin Y, Stremmel W 2005 The iron-regulatory peptide hormone hepcidin: expression and cellular localization in the mammalian kidney. J Endocrinol 184:361–370[Abstract/Free Full Text]
  19. Herrmann T, Muckenthaler M, van der Hoeven F, Brennan K, Gehrke SG, Hubert N, Sergi C, Grone HJ, Kaiser I, Gosch I, Volkmann M, Riedel HD, Hentze MW, Stewart AF, Stremmel W 2004 Iron overload in adult Hfe-deficient mice independent of changes in the steady-state expression of the duodenal iron transporters DMT1 and Ireg1/ferroportin. J Mol Med 82:39–48[CrossRef][Medline]
  20. Kulaksiz H, Gehrke SG, Janetzko A, Rost D, Bruckner T, Kallinowski B, Stremmel W 2004 Pro-hepcidin: expression and cell specific localisation in the liver and its regulation in hereditary haemochromatosis, chronic renal insufficiency, and renal anaemia. Gut 53:735–743[Abstract/Free Full Text]
  21. Harrison-Findik DD, Schafer D, Klein E, Timchenko NA, Kulaksiz H, Clemens D, Fein E, Andriopoulos B, Pantopoulos K, Gollan J 2006 Alcohol metabolism-mediated oxidative stress down-regulates hepcidin transcription and leads to increased duodenal iron transporter expression. J Biol Chem 281:22974–22982[Abstract/Free Full Text]
  22. Pietrangelo A, Caleffi A, Henrion J, Ferrara F, Corradini E, Kulaksiz H, Stremmel W, Andreone P, Garuti C 2005 Juvenile hemochromatosis associated with pathogenic mutations of adult hemochromatosis genes. Gastroenterology 128:470–479[CrossRef][Medline]
  23. Fein E, Merle U, Ehehalt R, Herrmann T, Kulaksiz H, Regulation of hepcidin in HepG2 and RINm5F cells. Peptides, in press
  24. Oudit GY, Trivieri MG, Khaper N, Liu PP, Backx PH 2006 Role of L-type Ca2+ channels in iron transport and iron-overload cardiomyopathy. J Mol Med 84:349–364[CrossRef][Medline]
  25. Balla G, Jacob HS, Balla J, Rosenberg M, Nath K, Apple F, Eaton JW, Vercellotti GM 1992 Ferritin: a cytoprotective antioxidant strategem of endothelium. J Biol Chem 267:18148–18153[Abstract/Free Full Text]
  26. Perriard JC, Hirschy A, Ehler E 2003 Dilated cardiomyopathy: a disease of the intercalated disc? Trends Cardiovasc Med 13:30–38[CrossRef][Medline]
  27. Basso C, Czarnowska E, Barbera MD, Bauce B, Beffagna G, Wlodarska EK, Pilichou K, Ramondo A, Lorenzon A, Wozniek O, Corrado D, Daliento L, Danieli GA, Valente M, Nava A, Thiene G, Rampazzo A 2006 Ultrastructural evidence of intercalated disc remodelling in arrhythmogenic right ventricular cardiomyopathy: an electron microscopy investigation on endomyocardial biopsies. Eur Heart J 27:1847–1854[Abstract/Free Full Text]
  28. Pilichou K, Nava A, Basso C, Beffagna G, Bauce B, Lorenzon A, Frigo G, Vettori A, Valente M, Towbin J, Thiene G, Danieli GA, Rampazzo A 2006 Mutations in desmoglein-2 gene are associated with arrhythmogenic right ventricular cardiomyopathy. Circulation 113:1171–1179[Abstract/Free Full Text]
  29. Gunshin H, Mackenzie B, Berger UV, Gunshin Y, Romero MF, Boron WF, Nussberger S, Gollan JL, Hediger MA 1997 Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 388:482–488[CrossRef][Medline]
  30. Fleming MD, Trenor III CC, Su MA, Foernzler D, Beier DR, Dietrich WF, Andrews NC 1997 Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nat Genet 16:383–386[CrossRef][Medline]
  31. Pietrangelo A 2004 Hereditary hemochromatosis—a new look at an old disease. N Engl J Med 350:2383–2397[Free Full Text]
  32. Ke Y, Chen YY, Chang YZ, Duan XL, Ho KP, Jiang de H, Wang K, Qian ZM 2003 Post-transcriptional expression of DMT1 in the heart of rat. J Cell Physiol 196:124–130[CrossRef][Medline]
  33. Frazer DM, Wilkins SJ, Becker EM, Vulpe CD, McKie AT, Trinder D, Anderson GJ 2002 Hepcidin expression inversely correlates with the expression of duodenal iron transporters and iron absorption in rats. Gastroenterology 123:835–844[CrossRef][Medline]
  34. Viatte L, Lesbordes-Brion JC, Lou DQ, Bennoun M, Nicolas G, Kahn A, Canonne-Hergaux F, Vaulont S 2005 Deregulation of proteins involved in iron metabolism in hepcidin-deficient mice. Blood 105:4861–4864[Abstract/Free Full Text]
  35. Nemeth E, Valore EV, Territo M, Schiller G, Lichtenstein A, Ganz T 2003 Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. Blood 101:2461–2463[Abstract/Free Full Text]
  36. Theurl I, Mattle V, Seifert M, Mariani M, Marth C, Weiss G 2006 Dysregulated monocyte iron homeostasis and erythropoietin formation in patients with anemia of chronic disease. Blood 107:4142–4148[Abstract/Free Full Text]
  37. Torti FM, Torti SV 2002 Regulation of ferritin genes and protein. Blood 99:3505–3516[Free Full Text]



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Q. Wang, F. Du, Z.-M. Qian, X. H. Ge, L. Zhu, W. H. Yung, L. Yang, and Y. Ke
Lipopolysaccharide Induces a Significant Increase in Expression of Iron Regulatory Hormone Hepcidin in the Cortex and Substantia Nigra in Rat Brain
Endocrinology, August 1, 2008; 149(8): 3920 - 3925.
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 J EndocrinolHome page
H. Kulaksiz, E. Fein, P. Redecker, W. Stremmel, G. Adler, and Y. Cetin
Pancreatic {beta}-cells express hepcidin, an iron-uptake regulatory peptide
J. Endocrinol., May 1, 2008; 197(2): 241 - 249.
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 haematolHome page
E. H.J.M. Kemna, H. Tjalsma, H. L. Willems, and D. W. Swinkels
Hepcidin: from discovery to differential diagnosis
Haematologica, January 1, 2008; 93(1): 90 - 97.
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