Loss of Cardiac Ferritin H Facilitates Cardiomyopathy via Slc7a11-Mediated Ferroptosis
By X. Fang, Zhaoxian Cai, Hao Wang, Dan Han, Qi Cheng, Pan Zhang, F. Gao, Yingying Yu, Zijun Song, Qian Wu and 8 more. Circulation Research, 2020
596 citations recorded by the source corpus.
Supplemental Digital Content is available in the text. Rationale: Maintaining iron homeostasis is essential for proper cardiac function. Both iron deficiency and iron overload are associated with cardiomyopathy and heart failure via complex mechanisms. Although ferritin plays a central role in iron metabolism by storing excess cellular iron, the molecular function of ferritin in cardiomyocytes remains unknown. Objective: To characterize the functional role of Fth (ferritin H) in mediating cardiac iron homeostasis and heart disease. Methods and Results: Mice expressing a conditional Fth knockout allele were crossed with 2 distinct Cre recombinase-expressing mouse lines, resulting in offspring that lack Fth expression specifically in myocytes (MCK-Cre) or cardiomyocytes (Myh6-Cre). Mice lacking Fth in cardiomyocytes had decreased cardiac iron levels and increased oxidative stress, resulting in mild cardiac injury upon aging. However, feeding these mice a high-iron diet caused severe cardiac injury and hypertrophic cardiomyopathy, with molecular features typical of ferroptosis, including reduced glutathione (GSH) levels and increased lipid peroxidation. Ferrostatin-1, a specific inhibitor of ferroptosis, rescued this phenotype, supporting the notion that ferroptosis plays a pathophysiological role in the heart. Finally, we found that Fth-deficient cardiomyocytes have reduced expression of the ferroptosis regulator Slc7a11, and overexpressing Slc7a11 selectively in cardiomyocytes increased GSH levels and prevented cardiac ferroptosis. Conclusions: Our findings provide compelling evidence that ferritin plays a major role in protecting against cardiac ferroptosis and subsequent heart failure, thereby providing a possible new therapeutic target for patients at risk of developing cardiomyopathy.
Subfields: Hematology, Nutrition and Dietetics, Pulmonary and Respiratory Medicine
View Paper: https://www.semanticscholar.org/paper/031fbe73b0bd52c36f230585d53dfa627f90ff1e
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In Pulmonary and Respiratory Medicine
Citations in the corpus
- The interaction between ferroptosis and lipid metabolism in cancer (2020, background): “Erastin and deleting SLC7A11 expression were not sufficient to induce macrophage ferroptosis unless under high iron conditions.(114,116) In addition, compared with M2 macrophages, M1 macrophages exert higher resistance to ferroptosis.”
- Lipid Peroxidation and Iron Metabolism: Two Corner Stones in the Homeostasis Control of Ferroptosis (2022, background): “Ferritin deficiency also induces ferroptosis via downregulation of solute carrier family 7 member 11 (SLC7A11), the inhibition of which triggers ferroptosis [33].”