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Published on: May 26, 2010
Characterization of the Genetic Program Linked to the Development of Atrial Fibrillation in CREM-IbΔC-X Mice
Matthias D Seidl1, Juliane Stein2, Sabine Hamer2
1From the Institute of Pharmacology and Toxicology, University of Münster, Germany (M.D.S., J.S., S.H., F.P., B.S., F.U.M.); Department of Genetic Epidemiology, Institute of Human Genetics, University of Münster, Germany (A.H., A.W., M.S.); Gerhard-Domagk-Institute of Pathology, University Hospital Münster, Germany (E.W.); Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, Germany (E.H., U.V.); and German Centre for Cardiovascular Research, Partner Site Greifswald, Germany (E.H., U.V.). seidl@uni-muenster.de.
Background:
Reduced expression of genes regulated by the transcription factors CREB/CREM (cAMP response element-binding protein/modulator) is linked to atrial fibrillation (AF) susceptibility in patients. Cardiomyocyte-directed expression of the inhibitory CREM isoform CREM-IbΔC-X in transgenic mice (TG) leads to spontaneous-onset AF preceded by atrial dilatation and conduction abnormalities. Here, we characterized the altered gene program linked to atrial remodeling and development of AF in CREM-TG mice.
Methods And Results:
Atria of young (TGy, before AF onset) and old (TGo, after AF onset) TG mice were investigated by mRNA microarray profiling in comparison with age-matched wild-type controls (WTy/WTo). Proteomic alterations were profiled in young mice (8 TGy versus 8 WTy). Annotation of differentially expressed genes revealed distinct differences in biological functions and pathways before and after onset of AF. Alterations in metabolic pathways, some linked to altered peroxisome proliferator-activated receptor signaling, muscle contraction, and ion transport were already present in TGy. Electron microscopy revealed significant loss of sarcomeres and mitochondria and increased collagen and glycogen deposition in TG mice. Alterations in electrophysiological pathways became prominent in TGo, concomitant with altered gene expression of K+-channel subunits and ion channel modulators, relevant in human AF.
Conclusions:
The most prominent alterations of the gene program linked to CREM-induced atrial remodeling were identified in the expression of genes related to structure, metabolism, contractility, and electric activity regulation, suggesting that CREM transgenic mice are a valuable experimental model for human AF pathophysiology.
Insights
Altered gene expression in cAMP response element-binding protein/modulator (CREM) transgenic mice reveals key changes in atrial structure, metabolism, and electrical activity, modeling human atrial fibrillation (AF) pathophysiology.
Area of Science:
- Cardiovascular Biology
- Molecular Genetics
- Cardiac Electrophysiology
Background:
- Reduced cAMP response element-binding protein/modulator (CREM) gene expression is linked to atrial fibrillation (AF) susceptibility.
- Cardiomyocyte-specific expression of inhibitory CREM isoform CREM-IbΔC-X in transgenic mice (TG) induces AF, atrial dilatation, and conduction abnormalities.
Purpose of the Study:
- Characterize the altered gene program associated with atrial remodeling and AF development in CREM-TG mice.
- Investigate temporal changes in gene expression and proteomic alterations before and after AF onset.
Main Methods:
- mRNA microarray profiling of atria from young (pre-AF) and old (post-AF) CREM-TG mice and age-matched wild-type controls.
- Proteomic profiling in young TG and wild-type mice.
- Electron microscopy to assess structural changes.
Main Results:
- Significant differences in biological functions and pathways were observed before and after AF onset in TG mice.
- Early alterations in metabolic pathways, muscle contraction, and ion transport were noted in young TG mice.
- Structural changes included loss of sarcomeres and mitochondria, increased collagen and glycogen deposition.
- Electrophysiological pathway alterations and changes in ion channel gene expression became prominent after AF onset.
Conclusions:
- CREM-induced atrial remodeling involves prominent alterations in genes regulating structure, metabolism, contractility, and electrical activity.
- CREM transgenic mice serve as a valuable model for studying human AF pathophysiology.
