Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, PR China.
Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, PR China.
J Cell Mol Med. 2020 Sep;24(18):10924-10934. doi: 10.1111/jcmm.15721. Epub 2020 Aug 14.
In the present study, we have investigated potential cardioprotective properties of Isosteviol analogue we recently synthesized and named JC105. Treatment of heart embryonic H9c2 cells with JC105 (10 μM) significantly increased survival of cells exposed to hypoxia-reoxygenation. JC105 (10 μM) activated ERK1/2, DRP1 and increased levels of cardioprotective SUR2A in hypoxia-reoxygenation, but did not have any effects on ERK1/2, DRP1 and/or SUR2A in normoxia. U0126 (10 μM) inhibited JC105-mediated phosphorylation of ERK1/2 and DRP1 without affecting AKT or AMPK, which were also not regulated by JC105. Seahorse bioenergetic analysis demonstrated that JC105 (10 μM) did not affect mitochondria at rest, but it counteracted all mitochondrial effects of hypoxia-reoxygenation. Cytoprotection afforded by JC105 was inhibited by U0126 (10 μM). Taken all together, these demonstrate that (a) JC105 protects H9c2 cells against hypoxia-reoxygenation and that (b) this effect is mediated via ERK1/2. The unique property of JC105 is that selectively activates ERK1/2 in cells exposed to stress, but not in cells under non-stress conditions.
在本研究中，我们研究了我们最近合成并命名为 JC105 的异甜醇类似物的潜在心脏保护特性。用 JC105（10 μM）处理心脏胚胎 H9c2 细胞可显著提高缺氧-复氧暴露细胞的存活率。JC105（10 μM）在缺氧-复氧时激活 ERK1/2、DRP1 并增加心脏保护 SUR2A 的水平，但对常氧下的 ERK1/2、DRP1 和/或 SUR2A 没有任何影响。U0126（10 μM）抑制 JC105 介导的 ERK1/2 和 DRP1 磷酸化，但不影响 AKT 或 AMPK，JC105 也不调节它们。 Seahorse 生物能量分析表明 JC105（10 μM）在静止时不影响线粒体，但它抵消了缺氧-复氧的所有线粒体作用。U0126（10 μM）抑制了 JC105 提供的细胞保护作用。综上所述，这些表明：（a）JC105 可保护 H9c2 细胞免受缺氧-复氧的影响；（b）这种作用是通过 ERK1/2 介导的。JC105 的独特之处在于它选择性地在应激细胞中激活 ERK1/2，但不在非应激条件下的细胞中激活。
