Activation of SphK1 by K6PC-5 Inhibits Oxygen-Glucose Deprivation/Reoxygenation-Induced Myocardial Cell Death
Activation of SphK1 by K6PC-5 Inhibits Oxygen-Glucose Deprivation/Reoxygenation-Induced Myocardial Cell Death
复制标题
DOI：
10.1089/dna.2015.2959
复制
发表时间：
2015-11-01
影响因子：
3.1
通讯作者：
Chen, Xin
中科院分区：
文献类型：
--
作者：
Shao, Jun-jie;Peng, Yi;Chen, Xin
在本研究中，我们评估了一种新的鞘氨醇激酶1（SphK 1）激活剂，K6 PC-5，对氧-葡萄糖剥夺（OGD）/复氧诱导的心肌细胞损伤的潜在影响。我们证明，K6 PC-5增加细胞内鞘氨醇-1-磷酸（S1 P）含量，并显着抑制OGD/再氧诱导的心肌细胞（H9 c2/HL-1细胞系和原代小鼠心肌细胞）死亡。SphK 1抑制剂，B-5354 c和SKI-II，或SphK 1-siRNA敲除不仅聚集OGD/再氧诱导的细胞毒性，而且使K6 PC-5的细胞保护无效。另一方面，SphK 1过表达减轻了OGD/复氧引起的H9 c2细胞死亡，并且K6 PC-5介导的细胞保护作用也在SphK 1过表达的细胞中增强。在分子水平上，OGD/复氧激活了线粒体死亡途径，表现为活性氧（ROS）产生、线粒体膜电位降低和p53-亲环蛋白D（Cyp-D）结合，这些都可通过K6 PC-5或SphK 1过表达缓解，但通过SphK 1敲除加剧。此外，OGD/复氧诱导心肌细胞中的促死亡神经酰胺产生，这在很大程度上被K6 PC-5抑制。同时，加入细胞可渗透的短链神经酰胺（C6）模拟OGD/复氧作用，诱导心肌细胞中ROS的产生和线粒体死亡途径。总之，我们得出结论，K6 PC-5可能通过激活SphK 1抑制OGD/再氧合诱导的心肌细胞死亡。研究结果表明，K6 PC-5对缺血性心脏病具有潜在的益处。
In the current study, we evaluated the potential effect of a novel sphingosine kinase 1 (SphK1) activator, K6PC-5, on oxygen-glucose deprivation (OGD)/reoxygenation-induced damages to myocardial cells. We demonstrated that K6PC-5 increased intracellular sphingosine-1-phosphate (S1P) content and remarkably inhibited OGD/reoxygenation-induced death of myocardial cells (H9c2/HL-1 lines and primary murine myocardiocytes). SphK1 inhibitors, B-5354c and SKI-II, or SphK1-siRNA knockdown not only aggregated OGD/reoxygenation-induced cytotoxicity but also nullified the cytoprotection by K6PC-5. On the other hand, overexpression of SphK1 alleviated H9c2 cell death by OGD/reoxygenation, and K6PC-5-mediated cytoprotection was also enhanced in SphK1 overexpressed cells. Molecularly, OGD/reoxygenation activated the mitochondrial death pathway, evidenced by reactive oxygen species (ROS) production, mitochondrial membrane potential reduction, and p53-cyclophilin D (Cyp-D) association, which were all alleviated by K6PC-5 or overexpression of SphK1, but exacerbated by SphK1 knockdown. Furthermore, OGD/reoxygenation induced prodeath ceramide production in myocardial cells, which was largely suppressed by K6PC-5. In the meantime, adding a cell-permeable short-chain ceramide (C6) mimicked OGD/reoxygenation actions and induced ROS production and the mitochondrial death pathway in myocardial cells. Together, we conclude that K6PC-5 inhibits OGD/reoxygenation-induced myocardial cell death probably through activating SphK1. The results of the study indicate a potential benefit of K6PC-5 on ischemic heart disease.