title: Nicorandil, a Nitric Oxide Donor and ATP-Sensitive Potassium Channel Opener, Protects Against Dystrophin-Deficient Cardiomyopathy.
abstract: Dystrophin-deficient cardiomyopathy is a growing clinical problem without targeted treatments. We investigated whether nicorandil promotes cardioprotection in human dystrophin-deficient induced pluripotent stem cell (iPSC)-derived cardiomyocytes and the muscular dystrophy mdx mouse heart.
  
  
  
  Dystrophin-deficient iPSC-derived cardiomyocytes had decreased levels of endothelial nitric oxide synthase and neuronal nitric oxide synthase. The dystrophin-deficient cardiomyocytes had increased cell injury and death after 2 hours of stress and recovery. This was associated with increased levels of reactive oxygen species and dissipation of the mitochondrial membrane potential. Nicorandil pretreatment was able to abolish these stress-induced changes through a mechanism that involved the nitric oxide-cyclic guanosine monophosphate pathway and mitochondrial adenosine triphosphate-sensitive potassium channels. The increased reactive oxygen species levels in the dystrophin-deficient cardiomyocytes were associated with diminished expression of select antioxidant genes and increased activity of xanthine oxidase. Furthermore, nicorandil was found to improve the restoration of cardiac function after ischemia and reperfusion in the isolated mdx mouse heart.
  
  
  
  Nicorandil protects against stress-induced cell death in dystrophin-deficient cardiomyocytes and preserves cardiac function in the mdx mouse heart subjected to ischemia and reperfusion injury. This suggests a potential therapeutic role for nicorandil in dystrophin-deficient cardiomyopathy.
authors.affiliation: Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Muhammad Z
authors.initials: MZ
authors.lastname: Afzal
authors.affiliation: Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Reiter
authors.affiliation: Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Courtney
authors.initials: C
authors.lastname: Gastonguay
authors.affiliation: Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Jered V
authors.initials: JV
authors.lastname: McGivern
authors.affiliation: Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Xuan
authors.initials: X
authors.lastname: Guan
authors.affiliation: Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Zhi-Dong
authors.initials: ZD
authors.lastname: Ge
authors.affiliation: Department of Rehabilitation Medicine, University of Washington, Seattle, WA, USA Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Mack
authors.affiliation: Department of Rehabilitation Medicine, University of Washington, Seattle, WA, USA Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Martin K
authors.initials: MK
authors.lastname: Childers
authors.affiliation: Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Allison D
authors.initials: AD
authors.lastname: Ebert
authors.affiliation: Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, USA Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA jstrande@mcw.edu.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Strande
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D002460:Cell Line; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D054086:KATP Channels / Q000819:agonists* / Q000378:metabolism; D008297:Male; D018101:Mice, Inbred mdx; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009137:Muscular Dystrophy, Animal / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020108:Nicorandil / Q000378:metabolism / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000378:metabolism / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D020127:Recovery of Function; D015398:Signal Transduction / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects; D014969:Xanthine Oxidase / Q000378:metabolism
chemical_list: D054086:KATP Channels; D020030:Nitric Oxide Donors; D017382:Reactive Oxygen Species; D020108:Nicorandil; D009569:Nitric Oxide; D014969:Xanthine Oxidase
keywords: cardiomyopathy; induced pluripotent cells; muscular dystrophy; nicorandil