SLC7A11/xCT Prevents Cardiac Hypertrophy by Inhibiting Ferroptosis
SLC7A11/xCT Prevents Cardiac Hypertrophy by Inhibiting Ferroptosis
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SLC7A11/xCT 通过抑制铁死亡来预防心脏肥大
DOI：
10.1007/s10557-021-07220-z
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发表时间：
2021-07-14
影响因子：
3.4
通讯作者：
Meng, Yan
中科院分区：
文献类型：
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作者：
Zhang, Xiyu;Zheng, Cuiting;Meng, Yan
目的全身性高血压可能引起左心室不良肥厚。病理性心脏肥大是心力衰竭的常见原因。我们研究了铁死亡抑制因子 xCT 在肥厚型心肌病中的意义。方法使用 qRT-PCR 和蛋白质印迹法测定血管紧张素 II (Ang II) 处理的小鼠心脏和大鼠心肌细胞中 xCT 的表达。 xCT 基因敲除小鼠及其野生型小鼠中，通过 Ang II 输注诱导心脏肥大。对这些小鼠的血压、心泵功能和心脏重塑的病理变化进行了分析。在 Ang II 处理的大鼠心肌细胞中检查细胞死亡、氧化应激和 xCT 介导的铁死亡。结果 Ang II 输注后，xCT 在 mRNA 和蛋白质水平上在第 1 天下调，但在第 14 天上调。在经 Ang II 处理的心肌细胞中，该值也有所降低，但在心成纤维细胞中则没有。 xCT 的抑制加剧了心肌细胞肥大，并提高了 Ang II 诱导的铁死亡生物标志物 Ptgs2、丙二醛和活性氧的水平，而 xCT 的过度表达则对抗这些有害影响。此外，敲除 xCT 会加剧 Ang II 介导的小鼠心脏纤维化、肥大和功能障碍。 Ferrostatin-1是一种铁死亡抑制剂，可减轻因抑制培养的大鼠细胞中的xCT或消除小鼠中的xCT而引起的心肌细胞肥大的加剧。结论xCT通过阻断铁死亡来抑制Ang II介导的心肌肥大。因此，xCT 的正向调节可能代表一种针对心脏肥厚性疾病的新治疗方法。
PurposeSystemic hypertension may induce adverse hypertrophy of the left cardiac ventricle. Pathological cardiac hypertrophy is a common cause of heart failure. We investigated the significance of ferroptosis repressor xCT in hypertrophic cardiomyopathy.MethodsxCT expression in angiotensin II (Ang II)-treated mouse hearts and rat cardiomyocytes was determined using qRT-PCR and Western blotting. Cardiac hypertrophy was induced by Ang II infusion in xCT knockout mice and their wildtype counterparts. Blood pressure, cardiac pump function, and pathological changes of cardiac remodeling were analyzed in these mice. Cell death, oxidative stress, and xCT-mediated ferroptosis were examined in Ang II-treated rat cardiomyocytes.ResultsAfter Ang II infusion, xCT was downregulated at day 1 but upregulated at day 14 at both mRNA and protein levels. It was also decreased in Ang II-treated cardiomyocytes, but not in cardiofibroblasts. Inhibition of xCT exacerbated cardiomyocyte hypertrophy and boosted the levels of ferroptosis biomarkers Ptgs2, malondialdehyde, and reactive oxygen species induced by Ang II, while overexpression of xCT opposed these detrimental effects. Furthermore, knockout of xCT aggravated Ang II-mediated mouse cardiac fibrosis, hypertrophy, and dysfunction. Ferrostatin-1, a ferroptosis inhibitor, alleviated the exacerbation of cardiomyocyte hypertrophy caused by inhibiting xCT in cultured rat cells or ablating xCT in mice.ConclusionxCT acts as a suppressor in Ang II-mediated cardiac hypertrophy by blocking ferroptosis. Positive modulation of xCT may therefore represent a novel therapeutic approach against cardiac hypertrophic diseases.