e in turnover of BCL family members. In summary, our results in the present study clearly indicate that treatment with nicorandil, the mitoK channel opener, appeared to reduce mitochondrial impairment and apoptotic cell death and prolonged survival in the R120G TG mice. Nicorandil can GLPG-0634 site inhibit the alteration of BCL2 and BAX in mitochondria in hearts from the R120G TG mice and can suppresses the mitochondrial death pathway through opening of the mitoK channel, which may be involved in it’s protective effect on DRM. Use of a mitoK channel opener such as nicorandil may represent a new therapeutic strategy for patients with DRM. Acknowledgments We would like to express our deepest gratitude to Dr. Jeffrey Robbins, Division of Molecular Cardiovascular Biology, Cincinnati Children’s Hospital Research Foundation, for his critical reading of the manuscript. Author Contributions Conceived and designed the experiments: AS. Performed the experiments: AS TM. Analyzed the data: AS TM KT. Contributed reagents/materials/ analysis tools: AS JY HN AT. Wrote the paper: AS. 12 April 2011 | Volume 6 | Issue 4 | e18922 Nicorandil and HSPB5 R120G Transgenic Mice 20. Bernardi P Mitochondrial transport of cations: channels, exchangers, and permeability transition. Physiol Rev 79: 1127155. 21. Halestrap AP, Clarke SJ, Javadov SA Mitochondrial permeability transition pore opening during myocardial reperfusion target for cardioprotection. Cardiovasc Res 61: 37285. 22. Wang L, Cherednichenko G, Hernandez L, Halow J, Camacho SA, et al. Preconditioning limits mitochondrial Ca during ischemia in rat hearts: role of K channels. Am J Physiol Heart Circ Physiol 280: H23212328. 23. Kowaltowski AJ, Seetharaman S, Paucek P, Garlid KD Bioenergetic consequences of opening the ATP-sensitive K channel of heart mitochondria. Am J Physiol Heart Circ Physiol 280: H64957. 24. Ardehali H, O’Rourke B, Marban E Cardioprotective role of the mitochondrial ATP-binding cassette protein 1. Circ Res 97: 74042. 25. Akao M, Ohler A, O’Rourke B, Marban E Mitochondrial ATP-sensitive potassium channels inhibit apoptosis induced by oxidative stress in cardiac cells. Circ Res 88: 1267275. 26. Shimizu S, Ide T, Yanagida T, Tsujimoto Y Electrophysiological study of a novel large pore formed by Bax and the 
voltage-dependent anion channel that is permeable to cytochrome c. J Biol Chem 275: 123212325. 27. Kirshenbaum LA, de Moissac D The bcl-2 gene product prevents programmed cell death of ventricular myocytes. Circulation 96: 1580585. 28. Tait SW, Green DR Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol 11: 62132. 29. Shimizu S, Narita M, Tsujimoto Y Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature 399: 48387. 30. Hai S, Takemura S, Minamiyama Y, Yamasaki K, Yamamoto S, et al. Mitochondrial K channel opener prevents ischemia-reperfusion injury in rat liver. Transplant Proc 37: 42831. 31. Maloyan A, Sayegh J, Osinska H, Chua BH, Robbins J Manipulation of death pathways in desmin-related cardiomyopathy. Circ Res 106: 1524532. 32. Kirsch DG, Doseff A, Chau BN, Lim DS, de Souza-Pinto NC, et al. Caspase-3-dependent cleavage of Bcl-2 promotes release of cytochrome c. J Biol Chem 274: 211551161. 13 April 2011 | Volume 6 | Issue 4 | e18922 Mutation Analysis of 2009 Pandemic Influenza A Viruses Collected in Japan during the Peak Phase of the Pandemic Jean-Etienne Morlighem1, Shintaro Aoki1, Mami Kishie in turnover of BCL family members. In summary, our results in the present study clearly indicate that treatment with nicorandil, the mitoK channel opener, appeared to reduce mitochondrial impairment and apoptotic cell death and prolonged survival in the R120G TG mice. Nicorandil can inhibit the alteration of BCL2 and BAX in mitochondria in hearts from the R120G TG mice and can suppresses the mitochondrial death pathway through opening of the mitoK channel, which may be involved in it’s protective effect on DRM. Use of a mitoK channel opener such as nicorandil may represent a new therapeutic strategy for patients with DRM. Acknowledgments We would like to express our deepest gratitude to Dr. Jeffrey Robbins, Division of Molecular Cardiovascular Biology, Cincinnati Children’s Hospital Research Foundation, for his critical reading of the manuscript. Author Contributions Conceived and designed the experiments: AS. Performed the experiments: AS TM. Analyzed the data: AS TM KT. Contributed reagents/materials/ analysis tools: AS JY HN AT. Wrote the paper: AS. 12 April 2011 | Volume 6 | Issue 4 | e18922 Nicorandil and HSPB5 R120G Transgenic Mice 20. Bernardi P Mitochondrial transport of cations: channels, exchangers, and permeability transition. Physiol Rev 79: 1127155. 21. Halestrap AP, Clarke SJ, Javadov SA Mitochondrial permeability transition pore opening during myocardial reperfusion target for cardioprotection. Cardiovasc Res 61: 37285. 22. Wang L, Cherednichenko G, Hernandez L, Halow J, Camacho SA, et al. Preconditioning limits mitochondrial Ca during ischemia in rat hearts: role of K channels. Am J Physiol Heart Circ Physiol 280: H23212328. 23. Kowaltowski AJ, Seetharaman S, Paucek P, Garlid KD Bioenergetic consequences of opening the ATP-sensitive K channel of heart mitochondria. Am J Physiol Heart Circ Physiol 280: H64957. 24. Ardehali H, O’Rourke B, Marban E Cardioprotective role of the mitochondrial ATP-binding cassette protein 1. Circ Res 97: 74042. 25. Akao M, Ohler A, O’Rourke B, Marban E Mitochondrial ATP-sensitive potassium channels inhibit apoptosis induced by oxidative stress in cardiac cells. Circ Res 88: 1267275. 26. Shimizu S, Ide T, Yanagida T, Tsujimoto Y Electrophysiological study of a novel large pore formed by Bax and the voltage-dependent anion channel that is permeable to cytochrome c. J Biol Chem 275: 123212325. 27. Kirshenbaum LA, de Moissac D The bcl-2 gene product prevents programmed cell death of ventricular myocytes. Circulation 96: 1580585. 28. Tait SW, Green DR Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol 11: 62132. 29. Shimizu S, Narita M, Tsujimoto Y Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature 399: 48387. 30. Hai S, Takemura S, Minamiyama Y, Yamasaki K, Yamamoto S, et al. Mitochondrial K channel opener prevents ischemia-reperfusion injury in rat liver. Transplant Proc 37: 42831. 31. Maloyan A, Sayegh J, Osinska H, Chua BH, Robbins J Manipulation of death pathways in desmin-related cardiomyopathy. Circ Res 106: 1524532. 32. Kirsch DG, Doseff A, Chau BN, Lim DS, de Souza-Pinto NC, et al. Caspase-3-dependent cleavage of Bcl-2 promotes release of cytochrome c. J Biol Chem 274: 211551161. 13 April 2011 | Volume 6 | Issue 4 | e18922 Mutation Analysis of 2009 Pandemic Influenza A Viruses Collected in Japan during the Peak Phase of the Pandemic Jean-Etienne Morlighem1, Shintaro Aoki1, Mami Kishi
