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Mitochondria-targeted (2-hydroxyamino-vinyl)-triphenyl-phosphonium releases NO and protects mouse embryonic cells against irradiation-induced apoptosis |
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| Authors: | Natalia A. Belikova,Jianfei Jiang,Detcho A. Stoyanovsky,Ashley Glumac,Hü lya Bayir,Joel S. Greenberger |
| Affiliation: | a Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA b Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15219, USA c Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA d Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA e Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA 15260, USA |
| Abstract: | Generation of reactive oxygen species by damaged respiratory chain followed by the formation of cytochrome c (cyt c)-cardiolipin (CL) complex with peroxidase activity are early events in apoptosis. By quenching the peroxidase activity of cyt c-CL complexes in mitochondria, nitric oxide can exert anti-apoptotic effects. Therefore, mitochondria-targeted pro-drugs capable of gradual nitric oxide radical (NO ) release are promising radioprotectants. Here we demonstrate that (2-hydroxyamino-vinyl)-triphenyl-phosphonium effectively accumulates in mitochondria, releases NO upon mitochondrial peroxidase reaction, protects mouse embryonic cells from irradiation-induced apoptosis and increases their clonogenic survival after irradiation. We conclude that mitochondria-targeted peroxidase-activatable NO-donors represent a new interesting class of radioprotectors. |
| Keywords: | HVTP, (2-hydroxyamino-vinyl)-triphenyl-phosphonium CL, cardiolipin TOCL, 1,1,2,2-tetraoleoyl cardiolipin PC, phosphatidylcholine ROS, reactive oxygen species cyt c, cytochrome c HPLC, high performance liquid chromatography NO |
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