title: Cardiac expression of the CREM repressor isoform CREM-IbΔC-X in mice leads to arrhythmogenic alterations in ventricular cardiomyocytes.
abstract: Chronic β-adrenergic stimulation is regarded as a pivotal step in the progression of heart failure which is associated with a high risk for arrhythmia. The cAMP-dependent transcription factors cAMP-responsive element binding protein (CREB) and cAMP-responsive element modulator (CREM) mediate transcriptional regulation in response to β-adrenergic stimulation and CREM repressor isoforms are induced after stimulation of the β-adrenoceptor. Here, we investigate whether CREM repressors contribute to the arrhythmogenic remodeling in the heart by analyzing arrhythmogenic alterations in ventricular cardiomyocytes (VCMs) from mice with transgenic expression of the CREM repressor isoform CREM-IbΔC-X (TG). Patch clamp analyses, calcium imaging, immunoblotting and real-time quantitative RT-PCR were conducted to study proarrhythmic alterations in TG VCMs vs. wild-type controls. The percentage of VCMs displaying spontaneous supra-threshold transient-like Ca(2+) releases was increased in TG accompanied by an enhanced transduction rate of sub-threshold Ca(2+) waves into these supra-threshold events. As a likely cause we discovered enhanced NCX-mediated Ca(2+) transport and NCX1 protein level in TG. An increase in I NCX and decrease in I to and its accessory channel subunit KChIP2 was associated with action potential prolongation and an increased proportion of TG VCMs showing early afterdepolarizations. Finally, ventricular extrasystoles were augmented in TG mice underlining the in vivo relevance of our findings. Transgenic expression of CREM-IbΔC-X in mouse VCMs leads to distinct arrhythmogenic alterations. Since CREM repressors are inducible by chronic β-adrenergic stimulation our results suggest that the inhibition of CRE-dependent transcription contributes to the formation of an arrhythmogenic substrate in chronic heart disease.
authors.affiliation: Institute of Pharmacology and Toxicology, University of Münster, Domagkstr. 12, 48149, Münster, Germany. j.s.schulte@uni-muenster.de.
authors.forename: J S
authors.initials: JS
authors.lastname: Schulte
authors.affiliation: Institute of Pharmacology and Toxicology, University of Münster, Domagkstr. 12, 48149, Münster, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Fehrmann
authors.affiliation: Institute of Pharmacology and Toxicology, University of Münster, Domagkstr. 12, 48149, Münster, Germany.
authors.forename: M A
authors.initials: MA
authors.lastname: Tekook
authors.affiliation: Institute of Pharmacology and Toxicology, University of Münster, Domagkstr. 12, 48149, Münster, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Kranick
authors.affiliation: Institute of Pharmacology and Toxicology, University of Münster, Domagkstr. 12, 48149, Münster, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Fels
authors.affiliation: Department of Molecular Physiology and Biophysics, Medicine (Cardiology), and Pediatrics, Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA.
authors.forename: N
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Molecular Physiology and Biophysics, Medicine (Cardiology), and Pediatrics, Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA.
authors.forename: X H T
authors.initials: XH
authors.lastname: Wehrens
authors.affiliation: Institute of Pharmacology and Toxicology, University of Münster, Domagkstr. 12, 48149, Münster, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Heinick
authors.affiliation: Institute of Pharmacology and Toxicology, University of Münster, Domagkstr. 12, 48149, Münster, Germany.
authors.forename: M D
authors.initials: MD
authors.lastname: Seidl
authors.affiliation: Institute of Pharmacology and Toxicology, University of Münster, Domagkstr. 12, 48149, Münster, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Schmitz
authors.affiliation: Institute of Pharmacology and Toxicology, University of Münster, Domagkstr. 12, 48149, Münster, Germany.
authors.forename: F U
authors.initials: FU
authors.lastname: Müller
mesh_terms: D000200:Action Potentials; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism* / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D051786:Cyclic AMP Response Element Modulator / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D006352:Heart Ventricles / Q000503:physiopathology; D007545:Isoproterenol; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism
chemical_list: C492004:Creb1 protein, mouse; C497411:Crem protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; C499849:NCX1 protein, mouse; D019831:Sodium-Calcium Exchanger; D051786:Cyclic AMP Response Element Modulator; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D007545:Isoproterenol; D011188:Potassium; D002118:Calcium
keywords: Arrhythmia; NCX; Remodeling; Transcription factor CREM
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