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Mitochondrial-derived Oxidative Stress Alters Gene Expression and DNA Methylation in the Heart

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE54896 | GEO | 2016/05/23

SECONDARY ACCESSION(S): PRJNA237982

REPOSITORIES: GEO

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Mitochondrial-derived Oxidative Stress Alters Gene Expression and DNA Methylation in the Heart [methylation]

Project description:Mitochondrial dysfunction causes oxidative stress and cardiomyopathy. Oxidative stress also is a side effect of dideoxynucleoside antiretrovirals (NRTI) and NRTI-induced cardiomyopathy. We show here that treatment with the NRTI AZT (1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione) modulates cardiac gene expression epigenetically through production of mitochondrially-derived reactive oxygen species (ROS). Transgenic mice with ubitquitous expression of mitochondrially-targeted catalase (MCAT) and C57BL/6 wild-type mice littermates (WT) were administered AZT (p.o., 0.22 mg/d; 35 days), and cardiac DNA and mRNA were isolated. In AZT-treated WT, 95 cardiac genes were differentially expressed compared to vehicle-treated WTs. When MCAT mice were treated with AZT, each of those 95 genes reverted to the pattern of vehicle-treated WTs. In AZT-treated WT hearts, Mthfr (5,10-methylenetetrahydrofolate reductase; a critical enzyme in synthesis of methionine cycle intermediates including S-adenosylmethionine (SAM)), was overexpressed. AZT caused hypermethylation (47%) and hypomethylation (53%) of differentially methylated DNA regions in WT cardiac DNA. AZT-treated MCAT heart DNA exhibited greater hypermethylation (91%) and less hypomethylation (9%) compared to vehicle-treated controls. Results show that mitochondrially-derived oxidative stress in the heart that is caused by AZT hinders cardiac DNA methylation, alters cardiac gene expression, and promotes characteristic pathophysiological changes of cardiomyopathy. This mechanism for NRTI toxicity offers insight into long-term side effects from these commonly used antiviral agents.

2016-05-23 | GSE54895 | GEO

Mitochondrial-derived Oxidative Stress Alters Gene Expression and DNA Methylation in the Heart [expression]

2016-05-23 | GSE54893 | GEO