Gene expression profile in dilated cardiomyopathy caused by elevated frequencies of mitochondrial DNA mutations in the mouse heart.
BACKGROUND
Elevated mitochondrial DNA (mtDNA) mutations are associated with aging and age-related diseases, but their pathogenic potential is unclear.


METHODS
We performed expression profiling using an Incyte cDNA array of a mouse model of elevated mtDNA mutations wherein random mutations accumulate specifically in the heart. At frequencies of about 1 mutation/10,000 base pairs, these mice show apoptosis of cardiomyocytes and development of four-chamber dilated cardiomyopathy.


RESULTS
Significant Analysis of Microarrays (SAM) revealed that 117 genes were altered in their expression in the transgenic (Tg) heart at a threshold of less than one false positive, of which 34 were up-regulated and 83 were down-regulated. Some of the changes were confirmed by Northern and Western blots. By classification of these genes into functional categories, we identified changes that reflected cardiac pathology. The results indicated that cardiomyopathy caused by mtDNA mutations was largely characterized by gene expression changes indicative of increased fibrosis and cardiac remodeling of the extracellular matrix. Few changes were observed, suggesting an alteration in either mitochondrial energy production or generation of increased oxidative stress.


CONCLUSIONS
Elevated frequencies of mtDNA mutations in the mouse heart lead to gene expression changes that are associated with remodeling of the extracellular matrix. Because cardiomyocytic death by apoptosis is also a feature of the dilated cardiomyopathy evident in these mice, extracellular remodeling may be a response to apoptotic signaling originating from the mitochondria with mtDNA mutations.
Zhang
Dekui
D
Department of Molecular Microbiology and Immunology, St. Louis University Health Science Center, 1402 South Grand Boulevard, Saint Louis, MO 63105, USA.
Ezekiel
Uthayashanker R
UR
Chang
Shin-Wen
SW
Zassenhaus
Hans Peter
HP
D000818:Animals; D017209:Apoptosis; D015152:Blotting, Northern; D015153:Blotting, Western; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004272:DNA, Mitochondrial / Q000235:genetics*; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D051379:Mice; D008929:Mitochondria, Heart / Q000235:genetics; D009154:Mutation; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism
D004272:DNA, Mitochondrial; D016326:Extracellular Matrix Proteins; D012333:RNA, Messenger