Project name: Mus musculus

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.Overall design: 15 left ventricle cardiac samples [4 vehicle (1%CMC)-treated wild-type C57BL/6, 3 AZT-treated wild-type C57BL/6, 4 vehicle-treated MCAT overexpressing, and 4 AZT-treated MCAT overexpressing) were collected, and RNA was extracted from each sample. Double-stranded cDNA was synthesized and hybridized to a 12X135 mouse expression array. Results were normalized and compared to DNA methylation array results from similar mouse groups. Each array represents a single mouse. All mice were of C57BL/6 background.

Data type: Transcriptome or Gene expression

Sample scope: Multiisolate

Relevance: ModelOrganism

Last updated: 2014-02-11