Heart disease remains the leading cause of death worldwide. Iron imbalance, whether deficiency or overload, contributes to heart failure. However, the molecular mechanisms governing iron homeostasis in the heart are poorly understood. Here, we demonstrate that mutation of bmp10, a heart-born morphogen crucial for embryonic heart development, results in severe anemia and cardiac hypertrophy in zebrafish. Initially, bmp10 deficiency causes cardiac iron deficiency, which later progresses to iron overload due to the dysregulated hepcidin/ferroportin axis in cardiac cells, leading to ferroptosis and heart failure. Early iron supplementation in bmp10-/- mutants rescues erythropoiesis, while iron chelation in juvenile fishes significantly alleviates cardiac hypertrophy. We further demonstrate that the interplay between HIF1α-driven hypoxic signaling and the IL6/p-STAT3 inflammatory pathways is critical for regulating cardiac iron metabolism. Our findings reveal BMP10 as a key regulator of iron homeostasis in the vertebrate heart and highlight the potential of targeting the BMP10-hepcidin-iron axis as a therapeutic strategy for iron-related cardiomyopathy.
|
Ambroszkiewicz, J., Klemarczyk, W., Mazur, J., Gajewska, J., Rowicka, G., Strucinska, M., Chelchowska, M., 2017. Serum hepcidin and soluble transferrin receptor in the assessment of iron metabolism in children on a vegetarian diet. Biol. Trace Elem. Res. 180, 182-190.
|
|
Andriopoulos Jr, B., Corradini, E., Xia, Y., Faasse, S.A., Chen, S., Grgurevic, L., Knutson, M.D., Pietrangelo, A., Vukicevic, S., Lin, H.Y., et al., 2009. BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism. Nat. Genet. 41, 482-487.
|
|
Ashby, D.R., Gale, D.P., Busbridge, M., Murphy, K.G., Duncan, N.D., Cairns, T.D., Taube, D.H., Bloom, S.R., Tam, F.W., Chapman, R., et al., 2010. Erythropoietin administration in humans causes a marked and prolonged reduction in circulating hepcidin. Haematologica 95, 505-508.
|
|
Babitt, J.L., Huang, F.W., Xia, Y., Sidis, Y., Andrews, N.C., Lin, H.Y., 2007. Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance. J. Clin. Invest. 117, 1933-1939.
|
|
Barbuti, A., Tessadori, F., van Weerd, J.H., Burkhard, S.B., Verkerk, A.O., de Pater, E., Boukens, B.J., Vink, A., Christoffels, V.M., Bakkers, J., 2012. Identification and functional characterization of cardiac pacemaker cells in zebrafish. PLoS One 7, e47644.
|
|
Brigelius-Flohe, R., Maiorino, M., 2013. Glutathione peroxidases. Biochim. Biophys. Acta 1830, 3289-3303.
|
|
Cai, X., Zhou, Z., Zhu, J., Liao, Q., Zhang, D., Liu, X., Wang, J., Ouyang, G., Xiao, W., 2020. Zebrafish Hif3α modulates erythropoiesis via regulation of gata1 to facilitate hypoxia tolerance. Development 147, 185116.
|
|
Capasso, T.L., Li, B., Volek, H.J., Khalid, W., Rochon, E.R., Anbalagan, A., Herdman, C., Yost, H.J., Villanueva, F.S., Kim, K., et al., 2020. BMP10-mediated ALK1 signaling is continuously required for vascular development and maintenance. Angiogenesis 23, 203-220.
|
|
Chen, H., Brady Ridgway, J., Sai, T., Lai, J., Warming, S., Chen, H., Roose-Girma, M., Zhang, G., Shou, W., Yan, M., 2013. Context-dependent signaling defines roles of BMP9 and BMP10 in embryonic and postnatal development. Proc. Natl. Acad. Sci. U.S.A. 110, 11887-11892.
|
|
Chen, H., Shi, S., Acosta, L., Li, W., Lu, J., Bao, S., Chen, Z., Yang, Z., Schneider, M.D., Chien, K.R., et al., 2004. BMP10 is essential for maintaining cardiac growth during murine cardiogenesis. Development 131, 2219-2231.
|
|
Chen, X., Li, X., Xu, X., Li, L., Liang, N., Zhang, L., Lv, J., Wu, Y.C., Yin, H., 2021. Ferroptosis and cardiovascular disease: role of free radical-induced lipid peroxidation. Free Radic. Res. 55, 405-415.
|
|
Cherif, H., Karlsson, T., 2014. Combination treatment with an erythropoiesis-stimulating agent and intravenous iron alleviates anaemia in patients with hereditary haemorrhagic telangiectasia. Ups. J. Med. Sci. 119, 350-353.
|
|
Chifman, J., Laubenbacher, R., Torti, S.V., 2014. A systems biology approach to iron metabolism. Adv. Exp. Med. Biol. 844, 201-225.
|
|
Choi, H., Kim, B.G., Kim, Y.H., Lee, S.J., Lee, Y.J., Oh, S.P., 2023. BMP10 functions independently from BMP9 for the development of a proper arteriovenous network. Angiogenesis 26, 167-186.
|
|
Chouvarine, P., Legchenko, E., Geldner, J., Riehle, C., Hansmann, G., 2019. Hypoxia drives cardiac miRNAs and inflammation in the right and left ventricle. J. Mol. Med. 97, 1427-1438.
|
|
Das, S.K., Wang, W., Zhabyeyev, P., Basu, R., McLean, B., Fan, D., Parajuli, N., DesAulniers, J., Patel, V.B., Hajjar, R.J., et al., 2015. Iron-overload injury and cardiomyopathy in acquired and genetic models is attenuated by resveratrol therapy. Sci. Rep. 5, 18132.
|
|
David, L., Mallet, C., Mazerbourg, S., Feige, J.J., Bailly, S., 2007. Identification of BMP9 and BMP10 as functional activators of the orphan activin receptor-like kinase 1 (ALK1) in endothelial cells. Blood 109, 1953-1961.
|
|
Doll, S., Proneth, B., Tyurina, Y.Y., Panzilius, E., Kobayashi, S., Ingold, I., Irmler, M., Beckers, J., Aichler, M., Walch, A., et al., 2017. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat. Chem. Biol. 13, 91-98.
|
|
Eltzschig, H.K., Bratton, D.L., Colgan, S.P., 2014. Targeting hypoxia signalling for the treatment of ischaemic and inflammatory diseases. Nat. Rev. Drug Discov. 13, 852-869.
|
|
Eyries, M., Montani, D., Nadaud, S., Girerd, B., Levy, M., Bourdin, A., Tresorier, R., Chaouat, A., Cottin, V., Sanfiorenzo, C., et al., 2019. Widening the landscape of heritable pulmonary hypertension mutations in paediatric and adult cases. Eur. Respir. J. 53,1801371.
|
|
Fang, X., Cai, Z., Wang, H., Han, D., Cheng, Q., Zhang, P., Gao, F., Yu, Y., Song, Z., Wu, Q., et al., 2020. Loss of cardiac ferritin h facilitates cardiomyopathy via slc7a11-mediated ferroptosis. Circ. Res. 127, 486-501.
|
|
Fang, X., Wang, H., Han, D., Xie, E., Yang, X., Wei, J., Gu, S., Gao, F., Zhu, N., Yin, X., et al., 2019. Ferroptosis as a target for protection against cardiomyopathy. Proc. Natl. Acad. Sci. U.S.A. 116, 2672-2680.
|
|
Fernandez-L, A., Sanz-Rodriguez, F., Blanco, FJ., Bernabeu, C., Botella, LM., 2006. Hereditary hemorrhagic telangiectasia, a vascular dysplasia affecting the TGF-β signaling pathway. Clin. Med. Res. 4, 66-78.
|
|
Hassannia, B., Vandenabeele, P., Vanden Berghe, T., 2019. Targeting ferroptosis to iron out cancer. Cancer Cell 35, 830-849.
|
|
Hentze, M.W., Muckenthaler, M.U., Galy, B., Camaschella, C., 2010. Two to tango: regulation of mammalian iron metabolism. Cell 142, 24-38.
|
|
Hilfiker-Kleiner, D., Shukla, P., Klein, G., Schaefer, A., Stapel, B., Hoch, M., Muller, W., Scherr, M., Theilmeier, G., Ernst, M., et al., 2010. Continuous glycoprotein-130-mediated signal transducer and activator of transcription-3 activation promotes inflammation, left ventricular rupture, and adverse outcome in subacute myocardial infarction. Circulation 122, 145-155.
|
|
Hodgson, J., Ruiz-Llorente, L., McDonald, J., Quarrell, O., Ugonna, K., Bentham, J., Mason, R., Martin, J., Moore, D., Bergstrom, K., et al., 2021. Homozygous GDF2 nonsense mutations result in a loss of circulating BMP9 and BMP10 and are associated with either PAH or an "HHT-like" syndrome in children. Mol. Genet. Genomic Med. 9, e1685.
|
|
Hu, C.J., Zhang, H., Laux, A., Pullamsetti, S.S., Stenmark, K.R., 2019. Mechanisms contributing to persistently activated cell phenotypes in pulmonary hypertension. J. Physiol. 597, 1103-1119.
|
|
Huang, J., Elicker, J., Bowens, N., Liu, X., Cheng, L., Cappola, T.P., Zhu, X., Parmacek, M.S., 2012. Myocardin regulates BMP10 expression and is required for heart development. J. Clin. Invest. 122, 3678-3691.
|
|
Jankowska, E.A., Drozd, M., Ponikowski, P., 2016. Iron deficiency in heart failure. Curr. Heart Fail. Rep. 3, 535-547.
|
|
Jankowska, E.A., Rozentryt, P., Witkowska, A., Nowak, J., Hartmann, O., Ponikowska, B., Borodulin-Nadzieja, L., Banasiak, W., Polonski, L., Filippatos, G., et al., 2010. Iron deficiency: an ominous sign in patients with systolic chronic heart failure. Eur. Heart J. 31, 1872-1880.
|
|
Jankowska, E.A., von Haehling, S., Anker, S.D., Macdougall, I.C., Ponikowski, P., 2013. Iron deficiency and heart failure: diagnostic dilemmas and therapeutic perspectives. Eur. Heart J. 34, 816-829.
|
|
Jeong, H.J., Hong, S.H., Park, R.K., Shin, T., An, N.H., Kim, H.M., 2005. Hypoxia-induced IL-6 production is associated with activation of MAP kinase, HIF-1, and NF-kappaB on HEI-OC1 cells. Hear. Res. 207, 59-67.
|
|
Kahr, P.C., Piccini, I., Fabritz, L., Greber, B., Scholer, H., Scheld, H.H., Hoffmeier, A., Brown, N.A., Kirchhof, P., 2011. Systematic analysis of gene expression differences between left and right atria in different mouse strains and in human atrial tissue. PLoS One 6, e26389.
|
|
Klip, I.T., Comin-Colet, J., Voors, A.A., Ponikowski, P., Enjuanes, C., Banasiak, W., Lok, D.J., Rosentryt, P., Torrens, A., Polonski, L., et al., 2013. Iron deficiency in chronic heart failure: an international pooled analysis. Am. Heart J. 165, 575-582.
|
|
Kobayashi, M., Suhara, T., Baba, Y., Kawasaki, N.K., Higa, J.K., Matsui, T., 2018. Pathological roles of iron in cardiovascular disease. Curr. Drug Targets 19, 1068-1076.
|
|
Koch, P.S., Olsavszky, V., Ulbrich, F., Sticht, C., Demory, A., Leibing, T., Henzler, T., Meyer, M., Zierow, J., Schneider, S., et al., 2017. Angiocrine Bmp2 signaling in murine liver controls normal iron homeostasis. Blood 129, 415-419.
|
|
Krause, A., Neitz, S., Magert, H.J., Schulz, A., Forssmann, W.G., Schulz-Knappe, P., Adermann, K., 2000. LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Lett. 480, 147-150.
|
|
Kulaksiz, H., Theilig, F., Bachmann, S., Gehrke, S.G., 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.
|
|
Lakhal-Littleton, S., Wolna, M., Chung, Y.J., Christian, H.C., Heather, L.C., Brescia, M., Ball, V., Diaz, R., Santos, A., Biggs, D., et al., 2016. An essential cell-autonomous role for hepcidin in cardiac iron homeostasis. Elife 5, 19804.
|
|
Lautenschlager, I., Pless-Petig, G., Middel, P., de Groot, H., Rauen, U., Stojanovic, T., 2018. Cold storage injury to rat small-bowel transplants-beneficial effect of a modified htk solution. Transplantation 102, 1666-1673.
|
|
Li, R., Xie, J., Xu, W., Zhang, L., Lin, H., Huang, W., 2022. LPS-induced PTGS2 manipulates the inflammatory response through trophoblast invasion in preeclampsia via NF-κB pathway. Reprod. Biol. 22, 100696.
|
|
Liu, J., Sun, B., Yin, H., Liu, S., 2016. Hepcidin: a promising therapeutic target for iron disorders: a systematic review. Medicine (Baltim.) 95, e3150.
|
|
Liu, X.B., Nguyen, N.B., Marquess, K.D., Yang, F., Haile, D.J., 2005. Regulation of hepcidin and ferroportin expression by lipopolysaccharide in splenic macrophages. Blood Cells Mol. Dis. 35, 47-56.
|
|
Ma, Z., Hu, J., Yu, G., Qin, J.G., 2017. Gene expression of bone morphogenetic proteins and jaw malformation in golden pompano trachinotus ovatuslarvae in different feeding regimes. J. Appl. Anim. Res. 46, 164-177.
|
|
Martin-Sanchez, D., Poveda, J., Fontecha-Barriuso, M., Ruiz-Andres, O., Sanchez-Nino, M.D., Ruiz-Ortega, M., Ortiz, A., Sanz, A.B., 2018. Targeting of regulated necrosis in kidney disease. Nefrologia 38, 125-135.
|
|
Merle, U., Fein, E., Gehrke, S.G., Stremmel, W., Kulaksiz, H., 2007. The iron regulatory peptide hepcidin is expressed in the heart and regulated by hypoxia and inflammation. Endocrinology 148, 2663-2668.
|
|
Meynard, D., Kautz, L., Darnaud, V., Canonne-Hergaux, F., Coppin, H., Roth, M.P., 2009. Lack of the bone morphogenetic protein BMP6 induces massive iron overload. Nat. Genet. 41, 478-481.
|
|
Nemeth, E., Ganz, T., 2006. Regulation of iron metabolism by hepcidin. Annu. Rev. Nutr. 26, 323-342.
|
|
Nemeth, E., Rivera, S., Gabayan, V., Keller, C., Taudorf, S., Pedersen, B.K., Ganz, T., 2004a. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J. Clin. Invest. 113, 1271-1276.
|
|
Nemeth, E., Tuttle, M.S., Powelson, J., Vaughn, M.B., Donovan, A., Ward, D.M., Ganz, T., Kaplan, J., 2004b. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306, 2090-2093.
|
|
Neuhaus, H., Rosen, V., Thies, R.S., 1999. Heart specific expression of mouse BMP-10 a novel member of the TGF-beta superfamily. Mech. Dev. 80, 181-184.
|
|
Nicolas, G., Bennoun, M., Porteu, A., Mativet, S., Beaumont, C., Grandchamp, B., Sirito, M., Sawadogo, M., Kahn, A., Vaulont, S., 2002. Severe iron deficiency anemia in transgenic mice expressing liver hepcidin. Proc. Natl. Acad. Sci. U.S.A. 99, 4596-4601.
|
|
Nishimura, N., Tanaka, T., Nishimura, Y., Shimada, Y., Zang, L., 2015. Repeated blood collection for blood tests in adult zebrafish. J. Vis. Exp. 102, e53272.
|
|
Oburoglu, L., Romano, M., Taylor, N., Kinet, S., 2016. Metabolic regulation of hematopoietic stem cell commitment and erythroid differentiation. Curr. Opin. Hematol. 23, 198-205.
|
|
Ouarne, M., Bouvard, C., Boneva, G., Mallet, C., Ribeiro, J., Desroches-Castan, A., Soleilhac, E., Tillet, E., Peyruchaud, O., Bailly, S., 2018. BMP9, but not BMP10, acts as a quiescence factor on tumor growth, vessel normalization and metastasis in a mouse model of breast cancer. J. Exp. Clin. Cancer Res. 37, 209.
|
|
Pagani, A., Nai, A., Corna, G., Bosurgi, L., Rovere-Querini, P., Camaschella, C., Silvestri, L., 2011. Low hepcidin accounts for the proinflammatory status associated with iron deficiency. Blood 118, 736-746.
|
|
Pashmforoush, M., Lu, J.T., Chen, H., Amand, T.S., Kondo, R., Pradervand, S., Evans, S.M., Clark, B., Feramisco, J.R., Giles, W., et al., 2004. Nkx2-5 pathways and congenital heart disease; loss of ventricular myocyte lineage specification leads to progressive cardiomyopathy and complete heart block. Cell 117, 373-386.
|
|
Qian, Z.M., Chang, Y.Z., Leung, G., Du, J.R., Zhu, L., Wang, Q., Niu, L., Xu, Y.J., Yang, L., Ho, K.P., et al., 2007. Expression of ferroportin1, hephaestin and ceruloplasmin in rat heart. Biochim. Biophys. Acta 1772, 527-532.
|
|
Qu, X., Liu, Y., Cao, D., Chen, J., Liu, Z., Ji, H., Chen, Y., Zhang, W., Zhu, P., Xiao, D., et al., 2019. BMP10 preserves cardiac function through its dual activation of SMAD-mediated and STAT3-mediated pathways. J. Biol. Chem. 294, 19877-19888.
|
|
Ramakrishnan, L., Pedersen, S.L., Toe, Q.K., Quinlan, G.J., Wort, S.J., 2018. Pulmonary arterial hypertension: iron matters. Front. Physiol. 9, 641.
|
|
Ruiz, S., Zhao, H., Chandakkar, P., Chatterjee, P.K., Papoin, J., Blanc, L., Metz, C.N., Campagne, F., Marambaud, P., 2016. A mouse model of hereditary hemorrhagic telangiectasia generated by transmammary-delivered immunoblocking of BMP9 and BMP10. Sci. Rep. 5, 37366.
|
|
Scott, S.P., Murray-Kolb, L.E., 2016. Iron status is associated with performance on executive functioning tasks in nonanemic young women. J. Nutr. 146, 30-37.
|
|
Sebastiani, G., Wilkinson, N., Pantopoulos, K., 2016. Pharmacological targeting of the hepcidin/ferroportin axis. Front. Pharmacol. 7, 160.
|
|
Silvestri, L., Nai, A., Dulja, A., Pagani, A., 2019. Hepcidin and the BMP-SMAD pathway: an unexpected liaison. Vitam. Horm. 110, 71-99.
|
|
Soon, E., Holmes, A.M., Treacy, C.M., Doughty, N.J., Southgate, L., Machado, R.D., Trembath, R.C., Jennings, S., Barker, L., Nicklin, P., et al., 2010. Elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension. Circulation 122, 920-927.
|
|
Sukumaran, A., Chang, J., Han, M., Mintri, S., Khaw, B.A., Kim, J., 2017. Iron overload exacerbates age-associated cardiac hypertrophy in a mouse model of hemochromatosis. Sci. Rep. 7, 5756.
|
|
Sun, S., Yang, S., Zhang, N., Yu, C., Liu, J., Feng, W., Xu, W., Mao, Y., 2023. Astragalus polysaccharides alleviates cardiac hypertrophy in diabetic cardiomyopathy via inhibiting the BMP10-mediated signaling pathway. Phytomedicine. 109, 154543.
|
|
Tanai, E., Frantz, S., 2015. Pathophysiology of heart failure. Compr. Physiol. 6, 187-214.
|
|
Tanaka, K., Honda, M., Takabatake, T., 2001. Redox regulation of MAPK pathways and cardiac hypertrophy in adult rat cardiac myocyte. J. Am. Coll. Cardiol. 37, 676-685.
|
|
Teichmann, U., Kessel, M., 2004. Highly restricted BMP10 expression in the trabeculating myocardium of the chick embryo. Dev. Gene. Evol. 214, 96-98.
|
|
Truksa, J., Peng, H., Lee, P., Beutler, E., 2007. Different regulatory elements are required for response of hepcidin to interleukin-6 and bone morphogenetic proteins 4 and 9. Br. J. Haematol. 139, 138-147.
|
|
Ueda, N., Takasawa, K., 2018. Impact of inflammation on ferritin, hepcidin and the management of iron deficiency anemia in chronic kidney disease. Nutrients 10, 1173.
|
|
van Breda, G.F., Bongartz, L.G., Zhuang, W., van Swelm, R.P., Pertijs, J., Braam, B., Cramer, M.J., Swinkels, D.W., Doevendans, P.A., Verhaar, M.C., et al., 2016. Cardiac hepcidin expression associates with injury independent of iron. Am. J. Nephrol. 44, 368-378.
|
|
Vela, D., 2018. Balance of cardiac and systemic hepcidin and its role in heart physiology and pathology. Lab. Invest. 98, 315-326.
|
|
Verga Falzacappa, M.V., Casanovas, G., Hentze, M.W., Muckenthaler, M.U., 2008. A bone morphogenetic protein (BMP)-responsive element in the hepcidin promoter controls HFE2-mediated hepatic hepcidin expression and its response to IL-6 in cultured cells. J. Mol. Med. 86, 531-540.
|
|
Wain, K.E., Ellingson, M.S., McDonald, J., Gammon, A., Roberts, M., Pichurin, P., Winship, I., Riegert-Johnson, D.L., Weitzel, J.N., Lindor, N.M., 2014. Appreciating the broad clinical features of SMAD4 mutation carriers: a multicenter chart review. Genet. Med. 16, 588-593.
|
|
Wang, H., An, P., Xie, E., Wu, Q., Fang, X., Gao, H., Zhang, Z., Li, Y., Wang, X., Zhang, J., et al., 2017. Characterization of ferroptosis in murine models of hemochromatosis. Hepatology 66, 449-465.
|
|
Wang, M.S., Huo, Y.X., Li, Y., Otecko, N.O., Su, L.Y., Xu, H.B., Wu, S.F., Peng, M.S., Liu, H.Q., Zeng, L., et al., 2016. Comparative population genomics reveals genetic basis underlying body size of domestic chickens. J. Mol. Cell Biol. 8, 542-552.
|
|
Wingert, R.A., Brownlie, A., Galloway, J.L., Dooley, K., Fraenkel, P., Axe, J.L., Davidson, A.J., Barut, B., Noriega, L., Sheng, X., et al., 2004. The chianti zebrafish mutant provides a model for erythroid-specific disruption of transferrin receptor 1. Development 131, 6225-6235.
|
|
Wofford, J.D., Chakrabarti, M., Lindahl, P.A., 2017. Mossbauer spectra of mouse hearts reveal age-dependent changes in mitochondrial and ferritin iron levels. J. Biol. Chem. 292, 5546-5554.
|
|
Xie, Y., Hou, W., Song, X., Yu, Y., Huang, J., Sun, X., Kang, R., Tang, D., 2016. Ferroptosis: process and function. Cell Death Differ. 23, 369-379.
|
|
Xin, Y., Gao, H., Wang, J., Qiang, Y., Imam, M.U., Li, Y., Wang, J., Zhang, R., Zhang, H., Yu, Y., et al., 2017. Manganese transporter Slc39a14 deficiency revealed its key role in maintaining manganese homeostasis in mice. Cell Discov. 3, 17025.
|
|
Xu, W., Barrientos, T., Mao, L., Rockman, Howard A., Sauve, Anthony A., Andrews, Nancy C., 2015. Lethal cardiomyopathy in mice lacking transferrin receptor in the heart. Cell Rep. 13, 533-545.
|
|
Yang, F., Dong, A., Mueller, P., Caicedo, J., Sutton, A.M., Odetunde, J., Barrick, C.J., Klyachkin, Y.M., Abdel-Latif, A., Smyth, S.S., 2012. Coronary artery remodeling in a model of left ventricular pressure overload is influenced by platelets and inflammatory cells. PLoS One 7, e40196.
|
|
Zhao, N., Zhang, A.S., Enns, C.A., 2013. Iron regulation by hepcidin. J. Clin. Invest. 123, 2337-2343.
|
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