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An essential cell-autonomous role for hepcidin in cardiac iron homeostasis
Samira Lakhal-Littleton1, Magda Wolna1, Yu Jin Chung1
1Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
Insights
Cardiomyocyte hepcidin regulates heart iron levels, preventing deficiency and dysfunction. This study reveals a cell-specific role for hepcidin in maintaining iron balance within heart cells.
Area of Science:
- Cardiovascular Biology
- Iron Metabolism
- Cellular Physiology
Background:
- Hepcidin is the primary regulator of systemic iron homeostasis, primarily acting on iron exporters like ferroportin in the gut and spleen.
- Ferroportin is present in cardiomyocytes, and its absence causes cardiac iron overload.
- The function of hepcidin within cardiomyocytes is currently unknown.
Purpose of the Study:
- To investigate the role of cardiomyocyte-expressed hepcidin in cardiac iron homeostasis.
- To determine the consequences of cardiomyocyte hepcidin deficiency or ferroportin resistance on cardiac function.
Main Methods:
- Generation of mice with cardiomyocyte-specific deletion of hepcidin.
- Generation of mice with cardiomyocyte-specific knock-in of hepcidin-resistant ferroportin.
- Assessment of systemic iron levels, cardiac iron content, and cardiac function.
Main Results:
- Mice lacking cardiomyocyte hepcidin or expressing hepcidin-resistant ferroportin maintained normal systemic iron levels.
- Both models developed severe cardiac iron deficiency.
- Cardiac-specific hepcidin deficiency or ferroportin resistance resulted in fatal contractile and metabolic dysfunction.
Conclusions:
- Cardiomyocyte hepcidin plays a crucial cell-autonomous role in maintaining cardiac iron homeostasis.
- Cardiac iron deficiency, independent of systemic iron levels, leads to severe heart dysfunction.
- This highlights a potential role for hepcidin-ferroportin interaction in other tissues expressing both proteins, such as the kidney and brain.
Abstract:
Hepcidin is the master regulator of systemic iron homeostasis. Derived primarily from the liver, it inhibits the iron exporter ferroportin in the gut and spleen, the sites of iron absorption and recycling respectively. Recently, we demonstrated that ferroportin is also found in cardiomyocytes, and that its cardiac-specific deletion leads to fatal cardiac iron overload. Hepcidin is also expressed in cardiomyocytes, where its function remains unknown. To define the function of cardiomyocyte hepcidin, we generated mice with cardiomyocyte-specific deletion of hepcidin, or knock-in of hepcidin-resistant ferroportin. We find that while both models maintain normal systemic iron homeostasis, they nonetheless develop fatal contractile and metabolic dysfunction as a consequence of cardiomyocyte iron deficiency. These findings are the first demonstration of a cell-autonomous role for hepcidin in iron homeostasis. They raise the possibility that such function may also be important in other tissues that express both hepcidin and ferroportin, such as the kidney and the brain.
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