A process that releases iron in response to stress may contribute to heart failure, and blocking this process could be a way of protecting the heart, suggests a study (“Iron derived from autophagy-mediated ferritin degradation induces cardiomyocyte death and heart failure in mice”) published in eLife.

People with heart failure often have an iron deficiency, leading some scientists to suspect that problems with iron processing in the body may play a role in this condition. The study explains one way that iron processing may contribute to heart failure and suggests potential treatment approaches to protect the heart.

“Although iron is necessary for metabolic homeostasis, it induces a programmed necrosis. Iron release from ferritin storage is through nuclear receptor coactivator 4 (NCOA4)-mediated autophagic degradation, known as ferritinophagy. However, the role of ferritinophagy in the stressed heart remains unclear. Deletion of Ncoa4 in mouse hearts reduced left ventricular chamber size and improved cardiac function along with the attenuation of the upregulation of ferritinophagy-mediated ferritin degradation 4 weeks after pressure overload,” write the investigators.

“Free ferrous iron overload and increased lipid peroxidation were suppressed in NCOA4-deficient hearts. A potent inhibitor of lipid peroxidation, ferrostatin-1, significantly mitigated the development of pressure overload-induced dilated cardiomyopathy in wild-type mice. Thus, the activation of ferritinophagy results in the development of heart failure, whereas inhibition of this process protects the heart against hemodynamic stress.”

“Iron is essential for many processes in the body including oxygen transport, but too much iron can lead to a build-up of unstable oxygen molecules that can kill cells,” says first author Jumpei Ito, PhD, who was a Research Associate at the School of Cardiovascular Medicine and Sciences, King’s College London, UK, at the time the study was carried out, and is now a visiting scientist based at Osaka Medical College, Japan. “We already knew that iron metabolism undergoes changes in heart failure, but it was unclear whether these changes are helpful or harmful.”

To learn more about the role of iron metabolism in heart failure, Ito and colleagues studied mice lacking a protein called the nuclear receptor coactivator 4 (NCOA4), which is necessary to release iron stored in cells when the body’s iron levels are low. They found that these mice developed less severe changes associated with heart failure compared to mice with NCOA4. Specifically, the NCOA4-deficient mice did not develop excessive levels of iron or a build-up of unstable oxygen molecules that can lead to apoptosis in heart failure.

Ferrostatin-1 inhibits the release of stored iron and reduces the accumulation of unstable oxygen molecules. Further experiments by the team showed that treating mice with NCOA4 with ferrostatin-1 can reduce the amount of apoptosis in heart failure.

“Our results suggest that the release of iron can be detrimental to the heart,” Ito says. “It can lead to unstable oxygen levels, death in heart cells and ultimately heart failure.”

More studies are now needed to understand each step in the process that releases iron and to test whether inhibiting this process could be beneficial to people with heart failure.

“Patients with heart failure who are iron deficient are currently treated with iron supplements, which previous studies have shown reduces their symptoms,” adds senior author Kinya Otsu, MD, PhD, the British Heart Foundation Professor of Cardiology at King’s College London. “While our work does not contradict those studies, it does suggest that reducing iron-dependent cell death in the heart could be a potential new treatment strategy for patients.”

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