Roxadustat通过激活HIF-1α介导的自噬来抑制铁下垂，从而改善胸主动脉夹层
Roxadustat Ameliorates Thoracic Aortic Dissection by Activating HIF-1α-Mediated Mitophagy to Inhibit Ferroptosis.
摘要(中文译文)
胸主动脉夹层（TAD）是一种危及生命的心血管疾病，药物治疗手段有限。血管平滑肌细胞（VSMC）丢失是TAD的关键病理特征。罗沙司他（ROX）是一种用于肾性贫血的HIF稳定剂，本研究在β-氨基丙腈（BAPN）诱导的TAD小鼠模型中对其进行了评估。ROX显著提高了生存率，减轻了体重下降和主动脉扩张，降低了TAD发生率，缓解了弹性纤维损伤，最终抑制了TAD进展。机制上，ROX上调HIF-1α表达，减少血管壁铁沉积和脂质过氧化产物（MDA、4-HNE），并使铁死亡标志物ACSL4、TFR1、GPX4和FTH1的异常表达恢复正常。在体外实验中，ROX减轻了Erastin/血管紧张素II诱导的VSMC铁死亡，通过提高氧消耗率（OCR）、恢复膜电位、减少活性氧（ROS）改善线粒体结构和功能，并通过上调HIF-1α和线粒体自噬标志物（PINK1、Parkin）促进线粒体自噬。HIF-1α抑制剂KC7F2和siHIF-1α可逆转上述效应。综上所述，本研究结果表明ROX通过促进HIF-1α表达增强线粒体自噬并抑制VSMC铁死亡，从而对TAD发挥保护作用，为TAD的预防和治疗提供了潜在的临床意义。
Abstract
Thoracic aortic dissection (TAD) is a life-threatening cardiovascular disease with limited pharmacological treatments. Vascular smooth muscle cell (VSMC) loss is a critical pathological feature of TAD. Roxadustat (ROX), a HIF stabilizer for renal anemia, was evaluated in a β-aminopropionitrile (BAPN)-induced TAD mouse model. It significantly improved survival, attenuated weight loss and aortic dilation, decreased the incidence of TAD, alleviated elastic fibers damage, and ultimately inhibited TAD progression. Mechanistically, ROX upregulated HIF-1α expression, reduced vascular wall iron deposition and lipid peroxidation products (MDA, 4-HNE), and normalized aberrant expression of ferroptosis markers ACSL4, TFR1, GPX4 and FTH1. In vitro, it mitigated Erastin/Ang II-induced VSMC ferroptosis, improved mitochondrial structure and function by enhancing oxygen consumption rate (OCR), restoring membrane potential, reducing reactive oxygen species (ROS), and boosting mitophagy via upregulating HIF-1α and mitophagy markers (PINK1, Parkin). The HIF-1α inhibitor KC7F2 and siHIF-1α reversed these effects. Taken together, our findings demonstrate that ROX protects against TAD by promoting HIF-1α expression to enhance mitophagy and inhibit VSMC ferroptosis, offering potential clinical implications for TAD prevention and treatment.
如何引用
AMA
Dan Zhao, Ziqi Chang, Qiong Han, Qiaoyu Wang, Yan Zhai, Mingfei Sun, et al. Roxadustat Ameliorates Thoracic Aortic Dissection by Activating HIF-1α-Mediated Mitophagy to Inhibit Ferroptosis.. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2026; doi:10.1096/fj.202600149R.
APA
Dan Zhao, Ziqi Chang, Qiong Han, Qiaoyu Wang, Yan Zhai, Mingfei Sun, et al (2026). Roxadustat Ameliorates Thoracic Aortic Dissection by Activating HIF-1α-Mediated Mitophagy to Inhibit Ferroptosis.. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. https://doi.org/10.1096/fj.202600149R
GB/T 7714
Dan Zhao, Ziqi Chang, Qiong Han, Qiaoyu Wang, Yan Zhai, Mingfei Sun, et al. Roxadustat Ameliorates Thoracic Aortic Dissection by Activating HIF-1α-Mediated Mitophagy to Inhibit Ferroptosis.[J]. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2026 doi:10.1096/fj.202600149R.
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