Ferroptosis is an iron-dependent form of cell death caused by the inactivation of glutathione peroxidase 4 (GPX4) and accumulation of lipid peroxides. Ferroptosis has been found to participate in the ischemia-reperfusion (I/R) injury, leading to heart dysfunction and myocardial cell death. Xanthohumol (XN), a prenylated flavonoid isolated from Humulus lupulus, has multiple pharmacological activities, such as anti-inflammatory and antioxidant. This study is aimed at investigating whether XN could attenuate the I/R-induced ferroptosis in cardiomyocytes and the underlying mechanisms. Cardiomyocytes were treated with Fe-SP and RSL3, and the rat hearts were treated with I/R. The results from the present study show that XN was able to protect cardiomyocytes against Fe-SP- and RSL3-induced ferroptotic cell death by decreasing the production of lipid peroxidation and ROS, chelating iron, reducing the NRF2 protein level, and modulating the protein levels of GPX4. Moreover, XN significantly decreased the mRNA levels of ferroptosis markers, Ptgs2 and Acsl4, and the protein levels of ACSL4 and NRF2 and modulated the protein levels of GPX4 in I/R-treated hearts. The findings from the present study suggest that XN might have the therapeutic potential for the I/R-induced ferroptosis injury.
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.
Catecholaminergic polymorphic ventricular tachycardia (CPVT), a rare autosomal dominant or recessive disease, usually results in syncope or sudden cardiac death. Most CPVT patients do not show abnormal cardiac structure and electrocardiogram features and symptoms, usually onset during adrenergically mediated physiological conditions. CPVT tends to occur at a younger age and is not easy to be diagnosed and managed. The main cause of CPVT is associated with mishandling Ca 2+ in cardiomyocytes. Intracellular Ca 2+ is strictly controlled by a protein located in the sarcoplasm reticulum (SR), such as ryanodine receptor, histidine-rich Ca 2+ -binding protein, triadin, and junctin. Mutation in these proteins results in misfolding or malfunction of these proteins, thereby affecting their Ca 2+ -binding affinity, and subsequently disturbs Ca 2+ homeostasis during excitation–contraction coupling (E-C coupling). Furthermore, transient disturbance of Ca 2+ homeostasis increases membrane potential and causes Ca 2+ store overload-induced Ca 2+ release, which in turn leads to delayed after depolarization and arrhythmia. Previous studies have focused on the interaction between ryanodine receptors and protein kinase or phosphatase in the cytosol. However, recent studies showed the regulation signaling for ryanodine receptor not only from the cytosol but also within the SR. The changing of Ca 2+ concentration is critical for protein interaction inside the SR which changes protein conformation to regulate the open probability of ryanodine receptors. Thus, it influences the threshold of Ca 2+ released from the SR, making it easier to release Ca 2+ during E-C coupling. In this review, we briefly discuss how Ca 2+ handling protein variations affect the Ca 2+ handling in CPVT.
Ascidians use a class of cysteine-rich proteins generally referred to as vanabins to reduce vanadium ions, one of the many biological processes that involve the redox conversion between disulfide and dithiolate mediated by transition-metal ions.To further understand the nature of disulfide/dithiolate exchange facilitated by a vanadium center, we report herein a six-coordinate non-oxido V IV complex containing an unbound disulfide moiety,with TEMPO (TEMPO = 2,2,6,6-tetramethylpiperidin-1-yl)oxyl) via hydrogen atom transfer. Importantly, complex 1 can be reduced by two electrons to form an eight-coordinate V IV complex, [V IV (PS3″) 2 ] 2− (4). The reaction can be reversed through a two-electron oxidation process to regenerate complex 1. The redox pathways both proceed through a common intermediate, [V(PS3″) 2 ] − (3), that has been previously reported as a resonance form of V V -dithiolate and a V IV -(thiolate)(thiyl-radical) species. This work demonstrates an unprecedented example of reversible disulfide/dithiolate interconversion mediated by a V IV center, as well as provides insights into understanding the function of V V reductases in vanabins.
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