Abstract 025: Oxidative-stress Mediates Apoptosis in a Human Model of Danon Disease and Heart Failure
Emerging evidence has highlighted the importance of autophagy, an intracellular recycling pathway, in regulating cardiomyocyte bioenergetics, function, and survival. However, the mechanisms responsible for cellular dysfunction and death in cardiomyocytes with impaired autophagic flux remain unclear. 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). To investigate the pathogenesis of Danon disease, we created iPS cells from a patient with a mutation in LAMP-2 who expired from heart failure. Danon iPS-derived cardiomyocytes recapitulated key features of the disease in vitro, including impaired autophagic flux, increased cell size, abnormal calcium handling, and increased expression of natriuretic peptides. Danon cells were noted to have significant amounts of mitochondrial oxidative stress and apoptosis, both of which could be abrogated by treatment with the antioxidant N-acetylcysteine. These results implicate mitochondrial oxidative stress and apoptosis in the pathogenesis of Danon disease. They also provide the basis for the use of antioxidants for Danon disease and other autophagy-related human diseases such as heart failure, diabetes, cancer, and neurodegenerative disorders.
- © 2013 by American Heart Association, Inc.