Bogomoletz Institute of Physiology, National Academy of Science, Bogomoletz Street, 4, Kyiv 01024, Ukraine.
Bogomoletz Institute of Physiology, National Academy of Science, Bogomoletz Street, 4, Kyiv 01024, Ukraine.
Life Sci. 2018 Jun 1;202:131-139. doi: 10.1016/j.lfs.2018.04.021. Epub 2018 Apr 13.
The aim of this study was to investigate the molecular mechanisms underlying the protective effects of hypoxia-inducible factor (HIF) signaling pathway activation in cardiomyocytes under anoxia-reoxygenation (A/R) injury. In this study, rat neonatal cardiomyocytes were pretreated with anti-Hif3A/Hif-3α siRNA or HIF-prolyl hydroxylase inhibitor prior to A/R injury. Our results showed that both HIF3A silencing and HIF-prolyl hydroxylase inhibition effectively increased the cell viability during A/R, led to changes in mRNA expression of HIF1-target genes, and reduced the loss of mitochondrial membrane potential (Δψ). Furthermore, application of anti-Hif3a siRNA led to an increase in mRNA expression of Epo, Igf1, Slc2a1/Glut-1, and Slc2a4/Glut-4. Similar results were observed with HIF-prolyl hydroxylase inhibition, which additionally upregulated the mRNA expression of Epor, Tert, and Pdk1. Hif3a RNA-interference and application of HIF-prolyl hydroxylase inhibitor during A/R modelling led to an increase of Δψ on 11.5 and 11.9 mV respectively, compared to the control groups. Thus, Hif3a RNA interference and HIF-prolyl hydroxylase inhibition protect cardiomyocytes against A/R injury via the HIF signaling pathway.
本研究旨在探讨缺氧诱导因子（HIF）信号通路激活在心肌细胞缺氧复氧（A/R）损伤中的保护作用的分子机制。在这项研究中，大鼠乳鼠心肌细胞在 A/R 损伤前用抗 Hif3A/Hif-3α siRNA 或 HIF-脯氨酰羟化酶抑制剂预处理。我们的结果表明，HIF3A 沉默和 HIF-脯氨酰羟化酶抑制均可有效增加 A/R 期间的细胞活力，导致 HIF1 靶基因的 mRNA 表达发生变化，并减少线粒体膜电位（Δψ）的丧失。此外，应用抗 Hif3a siRNA 导致 Epo、Igf1、Slc2a1/Glut-1 和 Slc2a4/Glut-4 的 mRNA 表达增加。HIF-脯氨酰羟化酶抑制也观察到类似的结果，其另外上调了 Epor、Tert 和 Pdk1 的 mRNA 表达。与对照组相比，在 A/R 模型形成过程中进行 Hif3a RNA 干扰和应用 HIF-脯氨酰羟化酶抑制剂可分别使 Δψ 增加 11.5 和 11.9 mV。因此，Hif3a RNA 干扰和 HIF-脯氨酰羟化酶抑制通过 HIF 信号通路保护心肌细胞免受 A/R 损伤。
