Abstract
Myocardial ischemia/reperfusion (I/R) injury has been associated with ferroptosis, which is characterized by an iron-dependent accumulation of lipid peroxide to lethal levels. Gossypol acetic acid (GAA), a natural product taken from the seeds of cotton plants, prevents oxidative stress. However, the effects of GAA on myocardial I/R-induced ferroptosis remain unclear. This study investigated the ability of GAA to attenuate I/R-induced ferroptosis in cardiomyocytes along with the underlying mechanisms in a well-established rat model of myocardial I/R and isolated neonatal rat cardiomyocytes. H9c2 cells and cardiomyocytes were treated with the ferroptosis inducers erastin, RSL3, and Fe-SP. GAA could protect H9c2 cells against ferroptotic cell death caused by these ferroptosis inducers by decreasing the production of malondialdehyde and reactive oxygen species, chelating iron content, and downregulating mRNA levels of Ptgs2. GAA could prevent oxygen-glucose deprivation/reperfusion-induced cell death and lipid peroxidation in the cardiomyocytes. Moreover, GAA significantly attenuated myocardial infarct size, reduced lipid peroxidation, decreased the mRNA levels of the ferroptosis markers Ptgs2 and Acsl4, decreased the protein levels of ACSL4 and NRF2, and increased the protein levels of GPX4 in I/R-induced ex vivo rat hearts. Thus, GAA may play a cytoprotectant role in ferroptosis-induced cardiomyocyte death and myocardial I/R-induced ferroptotic cell death.
Highlights
Fe-SP-induced lipid peroxidation (n = 4). (B) Gossypol acetic acid (GAA) significantly decreased the levels of prostaglandin-endoperoxide synthase 2 (Ptgs2) mRNAof
These results indicate that GAA decreases lipid peroxidation, maintains the protein levels of Glutathione peroxidase 4 (GPX4) and NRF2, and thereby attenuates I/R-induced ferroptotic cell death in ex vivo rat hearts
These results indicate that GAA decreases lipid peroxi12 of 15 dation, maintains the protein levels of GPX4 and NRF2, and thereby attenuates I/R-induced ferroptotic cell death in ex vivo rat hearts
Summary
Recent studies have shown that ferroptosis inhibitors, such as liproxstatin-1 (Lip-1) or ferrostatin-1 (Fer-1), and iron chelators, such as deferoxamine and dexrazoxane, can attenuate myocardial infarct size during cardiac ischemia/reperfusion (I/R) via suppression of ferroptosis [6,7,8]. Deferoxamine was shown to attenuate IRI-induced ferroptosis by reducing lipid peroxidation, iron content, and reversing GPX4 protein levels in rat hearts [8]. H9c2 cardiomyoblast cells were first used and treated with ferroptosis inducers, including erastin (Era), (1S,3R)-RSL3 (RSL3), and chlorido [N, Ndisalicylidene-1,2-phenylenediamine] iron (III) (Fe-SP). We confirm these inducers can effectively induce ferroptosis of H9c2 cells and clarify whether GAA have a protective effect against Era-, RSL3-, and Fe-SP-induced ferroptosis. I/R and to evaluate the possible mechanism of GAA’s protective effect
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