Division of Experimental Surgery, Department of Surgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, No. 707, Sec. 3, Zhongyang Rd., Hualien 97002, Taiwan.
Department of Physiology, School of Medicine, Tzu Chi University, No. 701, Sec. 3, Zhongyang Rd., Hualien 97004, Taiwan.
Biomolecules. 2021 Nov 10;11(11):1667. doi: 10.3390/biom11111667.
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 . 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 and , 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.
心肌缺血/再灌注 (I/R) 损伤与铁死亡有关，铁死亡的特征是脂质过氧化物在铁依赖性作用下积累到致死水平。棉酚乙酸（GAA）是一种从棉籽中提取的天然产物，可预防氧化应激。然而，GAA 对心肌 I/R 诱导的铁死亡的影响尚不清楚。本研究在心肌 I/R 大鼠模型和分离的新生大鼠心肌细胞中，研究了 GAA 减轻 I/R 诱导的心肌细胞铁死亡的能力及其潜在机制。用铁死亡诱导剂 erastin、RSL3 和 Fe-SP 处理 H9c2 细胞和心肌细胞。GAA 可以通过降低丙二醛和活性氧的产生、螯合铁含量以及下调 mRNA 水平，减少这些铁死亡诱导剂引起的 H9c2 细胞铁死亡。GAA 可以预防氧葡萄糖剥夺/再灌注诱导的心肌细胞死亡和脂质过氧化。此外，GAA 显著减轻了 I/R 诱导的离体大鼠心脏中的心肌梗死面积，降低了脂质过氧化水平，降低了铁死亡标志物 和 的 mRNA 水平，降低了 ACSL4 和 NRF2 的蛋白水平，增加了 GPX4 的蛋白水平。因此，GAA 可能在铁死亡诱导的心肌细胞死亡和心肌 I/R 诱导的铁死亡中发挥细胞保护作用。
