title: Cardioprotective effect of nicorandil, a mitochondrial ATP-sensitive potassium channel opener, prolongs survival in HSPB5 R120G transgenic mice.
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.
  
  
  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 death was observed. Cell viability was dose-dependently recovered in myocytes overexpressing HSPB5 R120G by treatment with nicorandil a mitochondrial ATP-sensitive potassium channel opener. Nicorandil treatment also inhibited the increase in BAX, the decrease in BCL2, activation of caspase-3 and apoptotic cell death by mutant HSPB5. To confirm the results of the in-vitro study, we analyzed the effect of nicorandil in HSPB5 R120G TG mice. Nicorandil treatment appeared to reduce mitochondrial impairment and apoptotic cell death and prolonged survival in HSPB5 R120G TG mice.
  
  
  CONCLUSIONS
  Nicorandil may prolong survival in HSPB5 R120G TG mice by protecting against mitochondrial impairments.
authors.affiliation: Department of Pharmacotherapeutics, School of Pharmacy, Iwate Medical University, Iwate, Japan. asanbe@iwate-med.ac.jp
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sanbe
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Marunouchi
authors.forename: Junji
authors.initials: J
authors.lastname: Yamauchi
authors.forename: Kouichi
authors.initials: K
authors.lastname: Tanonaka
authors.forename: Hideo
authors.initials: H
authors.lastname: Nishigori
authors.forename: Akito
authors.initials: A
authors.lastname: Tanoue
mesh_terms: D000256:Adenoviridae / Q000187:drug effects / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D005822:Genetic Vectors / Q000235:genetics; D015640:Ion Channel Gating / Q000187:drug effects*; D054086:KATP Channels / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D020125:Mutation, Missense / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020108:Nicorandil / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D016019:Survival Analysis; D038203:alpha-Crystallin B Chain / Q000235:genetics*
chemical_list: D051017:Apoptosis Regulatory Proteins; D002316:Cardiotonic Agents; C525420:Cryab protein, mouse; D054086:KATP Channels; D038203:alpha-Crystallin B Chain; D020108:Nicorandil; D045304:Cytochromes c