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Opening of the mitoKATP channel and decoupling of mitochondrial complex II and III contribute to the suppression of myocardial reperfusion hyperoxygenation |
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| Authors: | Bin Liu Xuehai Zhu Chwen-Lih Chen Keli Hu Harold M Swartz Yeong-Renn Chen Guanglong He |
| Institution: | 1. The Center for Biomedical EPR Spectroscopy and Imaging, Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, Columbus, OH, 43210, USA 2. Shantou University Medical College, Shantou, 515041, China 3. Key Laboratory of Organ Transplantation, Ministry of Education Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 4. Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, Columbus, OH, 43210, USA 5. Division of Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA 6. The EPR Center for the Study of Viable Systems, Dartmouth Medical School, Hanover, NH, USA 7. The Center for Biomedical EPR Spectroscopy and Imaging, Davis Heart and Lung Research Institute, Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University College of Medicine, 460 West 12th Avenue, 0388/BRT, Columbus, OH, 43210, USA 8. Davis Heart and Lung Research Institute, Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University College of Medicine, 460 West 12th Avenue, 0388/BRT, Columbus, OH, 43210, USA |
| Abstract: | Diazoxide, a mitochondrial ATP-sensitive potassium (mitoKATP) channel opener, protects the heart from ischemia–reperfusion injury. Diazoxide also inhibits mitochondrial complex II-dependent respiration in addition to its preconditioning effect. However, there are no prior studies of the role of diazoxide on post-ischemic myocardial oxygenation. In the current study, we determined the effect of diazoxide on the suppression of post-ischemic myocardial tissue hyperoxygenation in vivo, superoxide (O2 ??) generation in isolated mitochondria, and impairment of the interaction between complex II and complex III in purified mitochondrial proteins. It was observed that diazoxide totally suppressed the post-ischemic myocardial hyperoxygenation. With succinate but not glutamate/malate as the substrate, diazoxide significantly increased ubisemiquinone-dependent O2 ?? generation, which was not blocked by 5-HD and glibenclamide. Using a model system, the super complex of succinate-cytochrome c reductase (SCR) hosting complex II and complex III, we also observed that diazoxide impaired complex II and its interaction with complex III with no effect on complex III. UV–visible spectral analysis revealed that diazoxide decreased succinate-mediated ferricytochrome b reduction in SCR. In conclusion, our results demonstrated that diazoxide suppressed the in vivo post-ischemic myocardial hyperoxygenation through opening the mitoKATP channel and ubisemiquinone-dependent O2 ?? generation via inhibiting mitochondrial complex II-dependent respiration. |
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