Department of Cardiovascular Surgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi, China; Department of Cardiovascular Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi, China.
Department of Cardiovascular Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi, China.
Eur J Pharmacol. 2024 May 15;971:176524. doi: 10.1016/j.ejphar.2024.176524. Epub 2024 Mar 30.
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.
本研究旨在探讨白藜芦醇（Res）如何通过减轻铁死亡来发挥心肌保护作用。建立了体内和体外心肌缺血/再灌注损伤（MIRI）模型，并用或不用 Res 预处理。结果表明，Res 预处理有效减轻了 MIRI，表现为细胞活力增加、乳酸脱氢酶活性降低、梗死面积减少和心脏功能保持。此外，Res 预处理抑制了 MIRI 诱导的铁死亡，表现为线粒体完整性改善、谷胱甘肽水平升高、前列腺素内过氧化物合酶 2 水平降低、抑制铁过载和异常脂质过氧化。值得注意的是，Res 预处理降低或增加了电压依赖性阴离子通道 1/谷胱甘肽过氧化物酶 4（VDAC1/GPX4）的表达，这是通过缺氧/复氧（A/R）处理分别增加或减少的。然而，通过 pAd/VDAC1 过表达 VDAC1 和通过 Si-GPX4 敲低 GPX4 逆转了 Res 在 A/R 诱导的 H9c2 细胞中的保护作用，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，通过 Si-VDAC1 敲低 VDAC1 促进了 Res 对 A/R 诱导的 H9c2 细胞的保护作用和对 GPX4 的调节。最后，使用免疫共沉淀确定了 VDAC1 和 GPX4 之间的直接相互作用。总之，Res 预处理可通过 VDAC1/GPX4 信号通路保护心肌免受 MIRI 诱导的铁死亡。
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