Xuexian Fang1,2,3, Zhaoxian Cai1, Hao Wang3, Dan Han1, Qi Cheng1, Pan Zhang1, Feng Gao4, Yingying Yu1, Zijun Song1, Qian Wu1, Peng An2, Sicong Huang1, Jianwei Pan1, Hou-Zao Chen5, Jinghai Chen4, Andreas Linkermann6, Junxia Min1, Fudi Wang1,2,3. 1. From the First Affiliated Hospital, School of Public Health (X.F., Z.C., D.H., Q.C., P.Z., Y.Y., Z.S., Q.W., S.H., J.P., J.M., F.W.), Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China. 2. Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University (X.F., P.A., F.W.). 3. Department of Nutrition, Precision Nutrition Innovation Center, School of Public Health, Zhengzhou University, China (X.F., H.W., F.W.). 4. The Second Affiliated Hospital (F.G., J.C.), Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China. 5. Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (H.-Z.C.). 6. Division of Nephrology, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Germany (A.L.).
Abstract
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.
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.
Entities:
Keywords:
cardiomyopathies; ferritins; ferroptosis; heart failure; iron
Authors: Na Ta; Chuanren Qu; Hao Wu; Di Zhang; Tiantian Sun; Yanjun Li; Jun Wang; Xiaohui Wang; Tieshan Tang; Quan Chen; Lei Liu Journal: Proc Natl Acad Sci U S A Date: 2022-08-29 Impact factor: 12.779