title: Brief Report: Oxidative Stress Mediates Cardiomyocyte Apoptosis in a Human Model of Danon Disease and Heart Failure.
abstract: Danon disease is a familial cardiomyopathy associated with impaired autophagy due to mutations in the gene encoding lysosomal-associated membrane protein type 2 (LAMP-2). Emerging evidence has highlighted the importance of autophagy in regulating cardiomyocyte bioenergetics, function, and survival. However, the mechanisms responsible for cellular dysfunction and death in cardiomyocytes with impaired autophagic flux remain unclear. To investigate the molecular mechanisms responsible for Danon disease, we created induced pluripotent stem cells (iPSCs) from two patients with different LAMP-2 mutations. Danon iPSC-derived cardiomyocytes (iPSC-CMs) exhibited impaired autophagic flux and key features of heart failure such as increased cell size, increased expression of natriuretic peptides, and abnormal calcium handling compared to control iPSC-CMs. Additionally, Danon iPSC-CMs demonstrated excessive amounts of mitochondrial oxidative stress and apoptosis. Using the sulfhydryl antioxidant N-acetylcysteine to scavenge free radicals resulted in a significant reduction in apoptotic cell death in Danon iPSC-CMs. In summary, we have modeled Danon disease using human iPSC-CMs from patients with mutations in LAMP-2, allowing us to gain mechanistic insight into the pathogenesis of this disease. We demonstrate that LAMP-2 deficiency leads to an impairment in autophagic flux, which results in excessive oxidative stress, and subsequent cardiomyocyte apoptosis. Scavenging excessive free radicals with antioxidants may be beneficial for patients with Danon disease. In vivo studies will be necessary to validate this new treatment strategy.
authors.affiliation: Division of Cardiology, Department of Medicine.
authors.forename: Sherin I
authors.initials: SI
authors.lastname: Hashem
authors.affiliation: Division of Cardiology, Department of Medicine.
authors.forename: Cynthia N
authors.initials: CN
authors.lastname: Perry
authors.affiliation: Division of Cardiology, Department of Medicine.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Bauer
authors.affiliation: Division of Cardiology, Department of Medicine.
authors.forename: Sangyoon
authors.initials: S
authors.lastname: Han
authors.affiliation: Knight Cardiovascular Institute, Oregon Health Sciences University, Portland, Oregon, USA.
authors.forename: Stacey D
authors.initials: SD
authors.lastname: Clegg
authors.affiliation: Division of Cardiology, Department of Medicine.
authors.forename: Kunfu
authors.initials: K
authors.lastname: Ouyang
authors.affiliation: Division of Cardiology, Department of Medicine.
authors.forename: Dekker C
authors.initials: DC
authors.lastname: Deacon
authors.affiliation: Division of Cardiology, Department of Medicine.
authors.forename: Mary
authors.initials: M
authors.lastname: Spinharney
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California, USA.
authors.forename: Athanasia D
authors.initials: AD
authors.lastname: Panopoulos
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California, USA.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Izpisua Belmonte
authors.affiliation: Department of Pediatrics, University of California San Diego, San Diego, California, USA.|Institute for Genomic Medicine, University of California San Diego, San Diego, California, USA.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Frazer
authors.affiliation: Division of Cardiology, Department of Medicine.
authors.forename: Ju
authors.initials: J
authors.lastname: Chen
authors.affiliation: Knight Cardiovascular Institute, Oregon Health Sciences University, Portland, Oregon, USA.
authors.forename: Qiuming
authors.initials: Q
authors.lastname: Gong
authors.affiliation: Knight Cardiovascular Institute, Oregon Health Sciences University, Portland, Oregon, USA.
authors.forename: Zhengfeng
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Division of Cardiology, Department of Medicine.|Institute for Genomic Medicine, University of California San Diego, San Diego, California, USA.
authors.forename: Neil C
authors.initials: NC
authors.lastname: Chi
authors.affiliation: Division of Cardiology, Department of Medicine.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Adler
mesh_terms: D017209:Apoptosis; D001343:Autophagy; D052120:Glycogen Storage Disease Type IIb / Q000235:genetics* / Q000473:pathology; D006333:Heart Failure / Q000235:genetics* / Q000473:pathology; D006801:Humans; D057026:Induced Pluripotent Stem Cells; D032383:Myocytes, Cardiac / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics*
keywords: Apoptosis; Autophagy; Danon disease; Induced pluripotent stem cells; Oxidative stress
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