Abstract：
The present study aimed to explore how resveratrol (Res) confers myocardial protection by attenuating ferroptosis. In vivo and in vitro myocardial ischemia/reperfusion injury (MIRI) models were established, with or without Res pretreatment. The results showed that Res pretreatment effectively attenuated MIRI, as evidenced by increased cell viability, reduced lactate dehydrogenase activity, decreased infarct size, and maintained cardiac function. Moreover, Res pretreatment inhibited MIRI-induced ferroptosis, as shown by improved mitochondrial integrity, increased glutathione level, decreased prostaglandin-endoperoxide synthase 2 level, inhibited iron overload, and abnormal lipid peroxidation. Of note, Res pretreatment decreased or increased voltage-dependent anion channel 1/glutathione peroxidase 4 (VDAC1/GPX4) expression, which was increased or decreased via anoxia/reoxygenation (A/R) treatment, respectively. However, the overexpression of VDAC1 via pAd/VDAC1 and knockdown of GPX4 through Si-GPX4 reversed the protective effect of Res in A/R-induced H9c2 cells, whereas the inhibition of GPX4 with RSL3 abolished the protective effect of Res on mice treated with ischemia/reperfusion.Interestingly, knockdown of VDAC1 by Si-VDAC1 promoted the protective effect of Res on A/R-induced H9c2 cells and the regulation of GPX4. Finally, the direct interaction between VDAC1 and GPX4 was determined using co-immunoprecipitation. In conclusion, Res pretreatment could protect the myocardium against MIRI-induced ferroptosis via the VDAC1/GPX4 signaling pathway.
摘要：
本研究旨在探讨白藜芦醇（Res）如何通过减弱铁性凋亡来赋予心肌保护作用。建立体内和体外心肌缺血/再灌注损伤(MIRI)模型,有或没有Res预处理。结果表明,Res预处理能有效减弱MIRI,细胞活力增加证明了这一点，乳酸脱氢酶活性降低，梗死面积减小，维持心脏功能.此外，Res预处理抑制MIRI诱导的铁凋亡，如线粒体完整性改善所示，谷胱甘肽水平增加，前列腺素-内过氧化物合酶2水平降低，抑制铁过载，和异常的脂质过氧化。值得注意的是，Res预处理降低或增加电压依赖性阴离子通道1/谷胱甘肽过氧化物酶4（VDAC1/GPX4）表达，通过缺氧/复氧（A/R）治疗增加或减少，分别。然而,通过pAd/VDAC1过表达VDAC1和通过Si-GPX4敲低GPX4逆转了Res对A/R诱导的H9c2细胞的保护作用，而用RSL3抑制GPX4则消除了Res对缺血/再灌注小鼠的保护作用。有趣的是,Si-VDAC1敲除VDAC1促进Res对A/R诱导的H9c2细胞的保护作用和GPX4的调节。最后,VDAC1和GPX4之间的直接相互作用是使用免疫共沉淀确定的。总之,Res预处理可以通过VDAC1/GPX4信号通路保护心肌免受MIRI诱导的铁凋亡。
