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Physiol. Genomics (February 20, 2003). doi:10.1152/physiolgenomics.00172.2002
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Submitted on December 3, 2002
Accepted on February 17, 2003

Age-Related Impairment of the Transcriptional Responses to Oxidative Stress in the Mouse Heart

Michael G Edwards1, Deepayan Sarkar2, Roger G Klopp3, Jason D Marrow4, Richard H Weindruch5, and Tomas A Prolla1*

1 Department of Genetics and Medical Genetics, University of Wisconsin, Madison, WI, USA
2 Department of Statistics, University of Wisconsin, Madison, WI, USA
3 Veterans Administrative Hospital, University of Wisconsin, Madison, WI, USA
4 Department of Pharmacology and Medicine, Vanderbilt University, Nashville, TN, USA
5 Veterans Administrative Hospital, University of Wisconsin, Madison, WI, USA; Department of Medicine and Wisconsin Primate Research Center, University of Wisconsin, Madison, WI, USA

* To whom correspondence should be addressed. E-mail: taprolla{at}facstaff.wisc.edu.

To investigate the transcriptional response to oxidative stress in the heart and how it changes with age, we examined the cardiac gene expression profiles of young (5-month old), middle-aged (15-month old) and old (25-month old) C57Bl6/J mice treated with a single interperitoneal injection of paraquat (50 mg/kg). Mice were sacrificed at 0, 1, 3, 5 and 7 hours after paraquat treatment, and the gene expression profile was obtained with high-density oligonucleotide microarrays. Out of 9,977 genes represented on the microarray, 249 transcripts in the young mice, 298 transcripts in the middle-aged mice and 256 transcripts in the old mice displayed a significant change in mRNA levels (ANOVA, P<0.01). Among these, a total of 55 transcripts were determined to be paraquat-responsive for all age groups. Genes commonly induced in all age groups include those associated with stress, inflammatory, immune and growth factor responses. Interestingly, only young mice displayed a significant increase in expression of all three isoforms of GADD45, a DNA damage-responsive gene. Additionally, the number of immediate early genes (IEGs) found to be induced by paraquat was considerably higher in the younger animals. These results demonstrate that, at the transcriptional level, there is an age-related impairment of specific inducible pathways in the response to oxidative stress in the mouse heart.




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