Up-regulation of myocardial DNA base excision repair activities in experimental heart failure.
Base excision repair (BER) is the major pathway to counteract the genotoxic effect of endogenous DNA damaging agents. The present study investigated the enzymatic activities and gene transcription of DNA glycosylases initiating BER in an experimental heart failure (HF) model. Rats were subjected to myocardial infarction or sham-operated. Twenty-eight days after surgical intervention cell-free protein extracts, total RNA and genomic DNA were isolated to analyze DNA glycosylase and AP-endonuclease activities, transcript levels of DNA glycosylases and accumulation of oxidative DNA damage. The capacity to remove major oxidation products (e.g., formamidopyrimidine and 5-hydroxycytosine) was significantly increased in the border zone of infarcted area, while the capacity to remove the highly mutagenic 8-oxoguanine residue was enhanced both in non-infarcted and infarcted areas of left ventricle (LV). DNA glycosylase activities towards 3-methyladenine and uracil were up-regulated in infarcted and non-infarcted areas of LV, indicating that generation of alkylated and deaminated base lesions on DNA increase during HF. Finally, we found no difference in accumulation of oxidative DNA damage in myocardial tissue between rats with post-myocardial infarction and sham-operated rats. This up-regulation of activities, initiating the BER pathway, could play an important role during HF by counteracting the effect of genotoxic stress, structural damage of tissue and myocardial remodeling.
Yndestad
Arne
A
Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, University of Oslo, N-0027 Oslo, Norway.
Neurauter
Christine G
CG
Oie
Erik
E
Forstrøm
Rune J
RJ
Vinge
Leif E
LE
Eide
Lars
L
Luna
Luisa
L
Aukrust
Pål
P
Bjørås
Magnar
M
D000818:Animals; D004249:DNA Damage; D045647:DNA Glycosylases / Q000378:metabolism; D004260:DNA Repair; D004272:DNA, Mitochondrial / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D006333:Heart Failure / Q000235:genetics*; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation
D004272:DNA, Mitochondrial; C024829:8-hydroxyguanine; D006147:Guanine; D045647:DNA Glycosylases