title: Activation of SphK1 by K6PC-5 Inhibits Oxygen-Glucose Deprivation/Reoxygenation-Induced Myocardial Cell Death.
abstract: 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.
authors: 1 Department of Cardiothoracic Surgery, Nanjing First Hospital , Nanjing, China .
authors: Jun-jie
authors: JJ
authors: Shao
authors: 2 Department of Radiation and Medical Oncology, Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University , Wuhan, China .
authors: Yi
authors: Y
authors: Peng
authors: 1 Department of Cardiothoracic Surgery, Nanjing First Hospital , Nanjing, China .
authors: Li-ming
authors: LM
authors: Wang
authors: 1 Department of Cardiothoracic Surgery, Nanjing First Hospital , Nanjing, China .
authors: Jian-kai
authors: JK
authors: Wang
authors: 1 Department of Cardiothoracic Surgery, Nanjing First Hospital , Nanjing, China .
authors: Xin
authors: X
authors: Chen
mesh_terms: D000577:Amides / Q000494:pharmacology*; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line / Q000187:drug effects; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D010100:Oxygen / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D000099157:Sphingosine Kinase
chemical_list: D000577:Amides; D002518:Ceramides; D005947:Glucose; D010100:Oxygen; D017853:Phosphotransferases (Alcohol Group Acceptor); D000099157:Sphingosine Kinase; C531172:N-(1,3-dihydroxyisopropyl)-2-hexyl-3-oxodecanamide