bmp10 maintains cardiac function by regulating iron homeostasis

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 morphog...

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Bibliographic Details
Published in:Journal of genetics and genomics 2024-12, Vol.51 (12), p.1459-1473
Main Authors: Hu, Ruiqin, Li, Genfang, Hu, Peng, Niu, Hongbo, Li, Wenhao, Jiang, Shouwen, Guan, Guijun, Xu, Qianghua, Liu, Mingli, Chen, Liangbiao
Format: Article
Language:English
Subjects:
Anemia
Animals
bmp10
Bone Morphogenetic Proteins - genetics
Bone Morphogenetic Proteins - metabolism
Cardiac hypertrophy
Cardiomegaly - genetics
Cardiomegaly - metabolism
Cardiomegaly - pathology
Erythropoiesis - genetics
Ferroptosis
Heart
Hepcidins - genetics
Hepcidins - metabolism
Homeostasis - genetics
Inflammation
Iron
Iron - metabolism
Iron Overload - genetics
Iron Overload - metabolism
Iron Overload - pathology
Mutation
Myocardium - metabolism
Myocardium - pathology
Signal Transduction
Zebrafish - genetics
Zebrafish - metabolism
Zebrafish Proteins - genetics
Zebrafish Proteins - metabolism
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Summary: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.
ISSN:1673-8527
DOI:10.1016/j.jgg.2024.10.003