Qinghai Provincial People's Hospital, Xining, 810001, PR China.
Research Center for High Altitude Medicine, Qinghai University, Xining, 810001, PR China.
Int J Med Sci. 2021 Feb 4;18(7):1618-1627. doi: 10.7150/ijms.50804. eCollection 2021.
Hypoxia affects proliferation, differentiation, as well as death of cardiomyocyte, and plays an important role in the development of myocardial ischemia. However, the detailed mechanisms through which hypoxia regulates cardiomyocyte ferroptosis have not been explored. In this study, we revealed that hypoxia suppresses the proliferation, migration, and erastin-induced ferroptosis of H9c2 cells. First, we confirmed the upregulation of SENP1 in H9c2 cells cultured under hypoxic conditions. Through adenovirus-mediated SENP1 gene transfection, we demonstrated that SENP1 overexpression could enhance H9c2 cell proliferation and migration while also protecting H9c2 cells from erastin-induced ferroptosis. Furthermore, through immunoprecipitation and western blotting, we confirmed that SENP1 mediated deSUMOylation of HIF-1α and ACSL4 in H9c2 cells. In conclusion, this study describes the underlying mechanism through which hypoxia upregulates SENP1 expression, in turn protecting against ferroptosis via the regulation of HIF-1α and ACSL4 deSUMOylation. Our findings provide a theoretical foundation for the development of novel therapeutics for ischemic heart diseases.
缺氧影响心肌细胞的增殖、分化和死亡，在心肌缺血的发展中起重要作用。然而，缺氧调节心肌细胞铁死亡的详细机制尚未被探索。在这项研究中，我们揭示了缺氧抑制 H9c2 细胞的增殖、迁移和依马替尼诱导的铁死亡。首先，我们证实了缺氧培养的 H9c2 细胞中 SENP1 的上调。通过腺病毒介导的 SENP1 基因转染，我们证明 SENP1 的过表达可以增强 H9c2 细胞的增殖和迁移，同时保护 H9c2 细胞免受依马替尼诱导的铁死亡。此外，通过免疫沉淀和 Western blot，我们证实 SENP1 在 H9c2 细胞中介导了 HIF-1α 和 ACSL4 的去 SUMOylation。总之，本研究描述了缺氧上调 SENP1 表达的潜在机制，通过调节 HIF-1α 和 ACSL4 的去 SUMOylation 来防止铁死亡。我们的发现为缺血性心脏病的新型治疗方法的开发提供了理论基础。
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