Age-related impairment of the transcriptional responses to oxidative stress in the mouse heart.
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-mo-old), middle-aged (15-mo-old), and old (25-mo-old) C57BL/6 mice treated with a single intraperitoneal injection of paraquat (50 mg/kg). Mice were killed at 0, 1, 3, 5, and 7 h after paraquat treatment, and the gene expression profile was obtained with high-density oligonucleotide microarrays. 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 response 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.
Edwards
Michael G
MG
Department of Genetics and Medical Genetics, University of Wisconsin, Madison, Wisconsin 53706, USA.
Sarkar
Deepayan
D
Klopp
Roger
R
Morrow
Jason D
JD
Weindruch
Richard
R
Prolla
Tomas A
TA
D000375:Aging / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D054637:Dual-Specificity Phosphatases; D020869:Gene Expression Profiling / Q000379:methods; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D017781:Genes, Immediate-Early / Q000187:drug effects / Q000235:genetics; D016758:Genes, jun / Q000187:drug effects / Q000235:genetics; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D007274:Injections, Intraperitoneal; D047908:Intracellular Signaling Peptides and Proteins; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D018384:Oxidative Stress / Q000502:physiology*; D010269:Paraquat / Q000008:administration & dosage; D010749:Phosphoprotein Phosphatases; D014176:Protein Biosynthesis; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis; D011506:Proteins / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*; D000097642:GADD45 Proteins
D000975:Antioxidants; D054637:Dual-Specificity Phosphatases; D047908:Intracellular Signaling Peptides and Proteins; D010269:Paraquat; D010749:Phosphoprotein Phosphatases; D017027:Protein Tyrosine Phosphatases; D011506:Proteins; D000097642:GADD45 Proteins; C498844:Dusp14 protein, mouse