Loss of Cardiac Ferritin H Facilitates Cardiomyopathy via Slc7a11-Mediated Ferroptosis

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 ferritin H (Fth) in mediating cardiac iron homeostasis and heart disease. Methods and Results: Mice expressing a conditional Fth knockout allele were crossed with two 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.

The interaction between ferroptosis and lipid metabolism in cancer

“…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. 115 15-LOX modulates the ferroptotic endurance in macrophages, similar to that in tumor cells, 115,117 while solely knocking out 12/15-LOX is insufficient to prevent lipid peroxidation in T cells.…”

The Molecular Mechanisms of Iron Metabolism and Its Role in Cardiac Dysfunction and Cardioprotection

“…In contrast, targeting ferroptosis has been suggested as a feasible approach for managing these cardiac pathologies. Genetic manipulations in ferroptosis signaling, such as overexpression of Slc7a11, a key component of the cystine-glutamate antiporter [ 151 ], knockdown of Nrf2 , which regulates HO-1 expression [ 77 ] and depletion of GPX4 [ 132 ], have been shown to increase resistance against ferroptosis and alleviate damage of the heart and cardiac myocytes. Consistently with these results, pharmacological interventions, such as iron chelation, have also shown effective protection against iron-dependent processes of cell death.…”

“…Protective effects have been also demonstrated in other excess iron-induced cell death and ferroptosis models [ 149 ] using ferroptosis inhibitor ferrostatin-1 acting through scavenging of alkoxyl radicals produced by ferrous iron from lipid hydroperoxides [ 154 ]. In line, ferrostatin-1 exhibited beneficial effects in mice with cardiomyopathy due to FTH-deficiency [ 151 ].…”

“…Other interventions with anti-ferroptotic effects include activation of mTOR [ 149 ] and inhibition of HO-1, causing heme degradation with resultant release of free iron (inhibitor zinc protoporphyrin IX) [ 77 , 151 , 154 ], as well as other lipid peroxidation inhibitors (liproxstatin-1) [ 129 ]. In summary, these findings concerning ferroptosis confirm a paradigm of an important role of nonapoptotic cell death in the heart [ 130 , 155 , 156 , 157 ] and indicate that pharmacological interventions targeting one of these necrotic-like cell death modes or multi-target approaches can affect cardiovascular mortality at a greater extent than it is in the case of caspase modulation.…”

Revisiting Tumors and the Cardiovascular System: Mechanistic Intersections and Divergences in Ferroptosis

“…Fang et al verified that ferritin deficiency in cardiomyocytes promoted mild cardiac damage in mice, which progressed to hypertrophic cardiomyopathy when the mice were fed a high-iron diet. These cardiac injuries were reversed by SLC7A11 overexpression [89]. DOX mediates iron-replete ferroptosis via the nuclear translocation of Nrf2 and decomposition of HO-1 to induce cardiomyopathy and heart failure (HF) [29].…”