Matthias D Seidl1, Juliane Stein2, Sabine Hamer2, Florentina Pluteanu2, Beatrix Scholz2, Eva Wardelmann2, Andreas Huge2, Anika Witten2, Monika Stoll2, Elke Hammer2, Uwe Völker2, Frank U Müller2. 1. From 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. 2. From 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.).
Abstract
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.
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-TGmice. METHODS AND RESULTS: Atria of young (TGy, before AF onset) and old (TGo, after AF onset) TGmice 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 TGmice. Alterations in electrophysiological pathways became prominent in TGo, concomitant with altered gene expression of K+-channel subunits and ion channel modulators, relevant in humanAF. 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 CREMtransgenic mice are a valuable experimental model for humanAF pathophysiology.
Authors: Frank T Stümpel; Juliane Stein; Kirsten Himmler; Beatrix Scholz; Matthias D Seidl; Boris V Skryabin; Frank U Müller Journal: Front Pharmacol Date: 2018-07-05 Impact factor: 5.810
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Authors: Nils Bögeholz; Paul Pauls; Dirk G Dechering; Gerrit Frommeyer; Joshua I Goldhaber; Christian Pott; Lars Eckardt; Frank U Müller; Jan S Schulte Journal: Front Pharmacol Date: 2018-08-21 Impact factor: 5.810