cardioprotective effect of nicorandil, a mitochondrial atp-sensitive potassium channel opener, prolongs survival in hspb5 r120g transgenic micenicorandil保护作用,线粒体atp-sensitive钾通道揭幕战,延长生存hspb5 r120g转基因小鼠.pdfVIP

Cardioprotective Effect of Nicorandil, a Mitochondrial ATP-Sensitive Potassium Channel Opener, Prolongs Survival in HSPB5 R120G Transgenic Mice 1,2 3 2 3 1 Atsushi Sanbe *, Tetsuro Marunouchi , Junji Yamauchi , Kouichi Tanonaka , Hideo Nishigori , Akito Tanoue2 1 Department of Pharmacotherapeutics, School of Pharmacy, Iwate Medical University, Iwate, Japan, 2 Department of Pharmacology, National Research Institute for Child Health and Development, Tokyo, Japan, 3 Department of Pharmacology, Tokyo University of Pharmacy and Life Science, Tokyo, Japan Abstract Background: Transgenic (TG) mice with overexpression of an arg120gly (R120G) missense mutation in HSPB5 display desmin-related cardiomyopathy, which is characterized by formation of aggresomes. It is also known that progressive mitochondrial abnormalities and apoptotic cell death occur in the hearts of R120G TG mice. The role of mitochondrial dysfunction and apoptosis in disease progression, however, remains uncertain. Methods and Results: Mitochondrial abnormalities and apoptotic cell death induced by overexpression of HSPB5 R120G were analyzed in neonatal rat cardiomyocytes. Overexpression of mutant HSPB5 led to development of aggresomes with a concomitant reduction in cell viability in the myocytes. Overexpression of mutant HSPB5 induced a reduction in the cytochrome c level in the mitochondrial fraction and a corresponding increase in the cytoplasmic fraction in the myocytes. Down-regulation of BCL2 and up-regulation of BAX were detected in the myocytes expressing the mutant HSPB5. Concomitant with mitochondrial abnormality, the activation of caspase-3 and increased apoptotic cell d