Brief Report: Oxidative Stress Mediates Cardiomyocyte Apoptosis in a Human Model of Danon Disease and Heart Failure. (13th May 2015)

• Record Type: Journal Article
• Authors: Hashem, Sherin I.; Perry, Cynthia N.; Bauer, Matthieu; Han, Sangyoon; Clegg, Stacey D.; Ouyang, Kunfu; Deacon, Dekker C.; Spinharney, Mary; Panopoulos, Athanasia D.; Izpisua Belmonte, Juan Carlos; Frazer, Kelly A.; Chen, Ju; Gong, Qiuming; Zhou, Zhengfeng; Chi, Neil C.; Adler, Eric D.
• Is Part Of: Stem cells. Volume 33:Number 7(2015:Jul.)
• Page Start: 2343
• Page End: 2350
• Publication Date: 2015-05-13
• Subjects: Cloning -- Periodicals; Clone cells -- Periodicals; Stem cells -- Periodicals; Cell Differentiation -- Periodicals; Cell Division -- Periodicals; Clone Cells -- Periodicals; Hematopoietic Stem Cells -- Periodicals; Stem Cells -- Periodicals; 571.84
• DOI: 10.1002/stem.2015
• Languages: English
• ISSNs: 1066-5099

Abstract

<abstract abstract-type="main"> <title>Abstract</title> <p>Danon disease is a familial cardiomyopathy associated with impaired autophagy due to mutations in the gene encoding lysosomal‐associated membrane protein type 2 (<italic>LAMP‐2</italic>). 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 <italic>LAMP‐2</italic> 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 <italic>N</italic>‐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 <italic>LAMP‐2</italic>, 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. S<sc>tem</sc> C<sc>ells</sc> 2015;33:2343–2350</p> </abstract>