Abstract 16: Protective Effect of Nicorandil, a Mitochondrial ATP-Sensitive Potassium (mKATP) Channel Opener, on Mitochondrial Impairments Can Prolong Survival in Alpha-Beta-Crystallin R120G Transgenic Mice
Background: Transgenic (TG) mice with cardiac-specific overexpression of an arg120gly (R/G) missense mutation in alpha-beta-crystallin (CRYAB), display desmin-related cardiomyopathy (DRM), which is characterized by formation of aggresomes containing CRYAB and desmin. It is known that progressive mitochondrial abnormalities and apoptotic cell death occur in the hearts of R/G TG mice. The role of mitochondrial dysfunction and apoptosis in disease progression, however, remains uncertain.
Methods and Results: Mitochondrial abnormalities and apoptosis cell death induced by overexpression of CRYAB R/G was analyzed in neonatal rat cardiomyocytes. Overexpression of mutant CRYAB led to the development of CRYAB-positive aggresomes around nuclei with a concomitant reduction in cell viability in the myocytes. Overexpression of mutant CRYAB induced a reduction in the cytochrome c level in the mitochondrial fraction and an increase in it in the cytoplasmic fraction in the myocytes. Concomitant with mitochondrial abnormalities, the activation of caspase-3 and increased apoptotic cell death were observed in the cardiomyocytes overexpressing CRYAB R/G. These results suggest that mitochondrial impairment and apoptotic cell death may play a role in cardiac disease in DRM caused by CRYAB R/G. Cell viability was dose-dependently recovered in the myocytes overexpressing CRYAB R/G by treatment with nicorandil (Nico), a mitochondrial ATP-sensitive potassium (mKATP) channel opener. Nico treatment also inhibited the activation of caspase-3 and the apoptotic cell death by mutant CRYAB. These results suggest that the mKATP channel opener may protect against mitochondrial abnormalities, cellular toxicity and subsequent cell death, including apoptosis, in DRM. To confirm the results of the in vitro study, we analyzed the effect of nico in CRYAB R/G TG mice. Nico was orally administered to CRYAB R/G TG mice beginning at 22 weeks of age, at which time a slight cytochrome c release can be detected. Nico treatment appeared to reduce mitochondrial impairment and apoptotic cell death and prolonged survival in CRYAB R/G TG mice.
Conclusion: Nico, which is a mKATP channel opener, may prolong survival in CRYAB R/G TG mice by protecting against mitochondrial impairments.
- © 2010 by American Heart Association, Inc.