ferrostatin-1 and Cardiomyopathies

Trastuzumab (TRZ) is a first-line chemotherapeutic agent for HER-2 (ErbB2)-positive breast cancer. Unfortunately, its clinical use is limited due to its cardiotoxicity, referred to as TRZ-induced cardiotoxicity (TIC). However, the exact molecular mechanisms underlying the development of TIC remain unclear. Iron and lipid metabolism and redox reactions participate in the development of ferroptosis. Here, we show that ferroptosis-mediated mitochondrial dysfunction is involved in TIC in vivo and in vitro. We first established TIC models with BALB/c mice or neonatal rat cardiomyocytes and confirmed cardiomyopathy with echocardiography and inhibition of cell viability with a cell counting kit-8 examination, respectively. We showed that TRZ downregulated glutathione peroxidase 4 (GPx4) and elevated lipid peroxidation by-products, 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), by inactivating the ErbB2/PI3K/AKT/Nrf2 signalling pathway. Additionally, upregulated mitochondrial 4-HNE binds to voltage-dependent anion channel 1 (VDAC1), increases VDAC1 oligomerization, and subsequently induces mitochondrial dysfunction, as evidenced by mitochondrial permeability transition pore (mPTP) opening and decreased mitochondrial membrane potential (MMP) and ATP levels. Concomitantly, TRZ affected the mitochondrial levels of GSH/GSSG and iron ions and the stability of mitoGPx4. Ferroptosis inhibitors, such as ferrostatin-1 (Fer-1) or the iron chelator deferoxamine (DFO), ameliorate TRZ-induced cardiomyopathy. Overexpression of mitoGPx4 also suppressed mitochondrial lipid peroxidation and prevented TRZ-induced ferroptosis. Our study strongly suggests that targeting ferroptosis-mediated mitochondrial dysfunction is a potential cardioprotective strategy.

Topics: Animals; Antineoplastic Agents, Immunological; Cardiomyopathies; Female; Ferroptosis; Iron; Lipid Peroxidation; Mice; Mice, Inbred BALB C; Mitochondria; Myocytes, Cardiac; Phospholipid Hydroperoxide Glutathione Peroxidase; Rats; Specific Pathogen-Free Organisms; Trastuzumab

Iron overload cardiomyopathy (IOC) is the leading cause of death in cases of iron overload in patients. Previous studies demonstrated that iron overload led to cardiomyocyte dysfunction and death through multiple pathways including apoptosis, necroptosis and ferroptosis. However, the dominant cell death pathway in the iron-overloaded heart needs clarification. We tested the hypothesis that ferroptosis, an iron-dependent cell death, plays a dominant role in IOC, and ferroptosis inhibitor exerts greater efficacy than inhibitors of apoptosis and necroptosis on improving cardiac function in iron-overloaded rats. Iron dextran was injected intraperitoneally into male Wistar rats for four weeks to induce iron overload. Then, the rats were divided into 5 groups: treated with vehicle, apoptosis inhibitor (z-VAD-FMK), necroptosis inhibitor (Necrostatin-1), ferroptosis inhibitor (Ferrostatin-1) or iron chelator (deferoxamine) for 2 weeks. Cardiac function, mitochondrial function, apoptosis, necroptosis and ferroptosis were determined. The increased expression of apoptosis-, necroptosis- and ferroptosis-related proteins, were associated with impaired cardiac and mitochondrial function in iron-overloaded rats. All cell death inhibitors attenuated cardiac apoptosis, necroptosis and ferroptosis in iron-overloaded rats. Ferrostatin-1 was more effective than the other drugs in diminishing mitochondrial dysfunction and Bax/Bcl-2 ratio. Moreover, both Ferrostatin-1 and deferoxamine reversed iron overload-induced cardiac dysfunction as indicated by restored left ventricular ejection fraction and E/A ratio, whereas z-VAD-FMK and Necrostatin-1 only partially improved this parameter. These results indicated that ferroptosis could be the predominant form of cardiomyocyte death in IOC, and that inhibiting ferroptosis might be a potential novel treatment for IOC.

Topics: Animals; Apoptosis; Cardiomyopathies; Deferoxamine; Ferroptosis; Humans; Iron; Iron Overload; Male; Mitochondria; Myocytes, Cardiac; Necroptosis; Rats; Rats, Wistar; Stroke Volume; Ventricular Function, Left

Heart failure is a major public health problem, and abnormal iron metabolism is common in patients with heart failure. 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

Topics: Animals; Aorta; Autophagy; Cardiomyopathies; Constriction; Cyclohexylamines; Disease Models, Animal; Ferritins; Heart Failure; Iron; Lipid Peroxidation; Male; Mice, Inbred C57BL; Mice, Transgenic; Myocytes, Cardiac; Nuclear Receptor Coactivators; Phenylenediamines

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.. To characterize the functional role of Fth (ferritin H) in mediating cardiac iron homeostasis and heart disease.. Mice expressing a conditional Fth knockout allele were crossed with 2 distinct Cre recombinase-expressing mouse lines, resulting in offspring that lack. 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.

Topics: Aging; Alleles; Amino Acid Transport System y+; Animals; Apoferritins; Cardiomyopathies; Cardiomyopathy, Hypertrophic; Crosses, Genetic; Cyclohexylamines; Ferroptosis; Glutathione; Heart Failure; Homeostasis; Hypertrophy, Left Ventricular; Iron; Iron Deficiencies; Iron Overload; Iron, Dietary; Lipid Peroxidation; Male; Mice; Mice, Transgenic; Myocardium; Myocytes, Cardiac; Oxidative Stress; Phenylenediamines; Reactive Oxygen Species