title: Dysregulated IER3 Expression is Associated with Enhanced Apoptosis in Titin-Based Dilated Cardiomyopathy.
abstract: Apoptosis (type I programmed cell death) of cardiomyocytes is a major process that plays a role in the progression of heart failure. The early response geneIER3regulates apoptosis in a wide variety of cells and organs. However, its role in heart failure is largely unknown. Here, we investigate the role ofIER3in an inducible heart failure mouse model. Heart failure was induced in a mouse model that imitates a human titin truncation mutation we found in a patient with dilated cardiomyopathy (DCM). Transferase dUTP nick end labeling (TUNEL) and ssDNA stainings showed induction of apoptosis in titin-deficient cardiomyocytes during heart failure development, whileIER3response was dysregulated. Chromatin immunoprecipitation and knock-down experiments revealed that IER3 proteins target the promotors of anti-apoptotic genes and act as an anti-apoptotic factor in cardiomyocytes. Its expression is blunted during heart failure development in a titin-deficient mouse model. Targeting theIER3pathway to reduce cardiac apoptosis might be an effective therapeutic strategy to combat heart failure.
authors.affiliation: Department of Cardiology and Cardiovascular Diseases, Eberhard Karls University, 72076 Tübingen, Germany. zhouqf09@gmail.com.
authors.forename: Qifeng
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Department of Cardiology and Cardiovascular Diseases, Eberhard Karls University, 72076 Tübingen, Germany. hahnjk@gmail.com.
authors.forename: Julia Kelley
authors.initials: JK
authors.lastname: Hahn
authors.affiliation: Department of Cardiology and Cardiovascular Diseases, Eberhard Karls University, 72076 Tübingen, Germany. Balram.Neupane@med.uni-tuebingen.de.
authors.forename: Balram
authors.initials: B
authors.lastname: Neupane
authors.affiliation: Department of Cardiology and Cardiovascular Diseases, Eberhard Karls University, 72076 Tübingen, Germany. parwez.aidery@med.uni-tuebingen.de.
authors.forename: Parwez
authors.initials: P
authors.lastname: Aidery
authors.affiliation: Institute for Integrative Pathophysiology, Universitätsmedizin Mannheim, 68167 Mannheim, Germany. labeit@medma.de.
authors.forename: Siegfried
authors.initials: S
authors.lastname: Labeit
authors.affiliation: Department of Cardiology and Cardiovascular Diseases, Eberhard Karls University, 72076 Tübingen, Germany. meinrad.gawaz@med.uni-tuebingen.de.
authors.forename: Meinrad
authors.initials: M
authors.lastname: Gawaz
authors.affiliation: Department of Cardiology and Cardiovascular Diseases, Eberhard Karls University, 72076 Tübingen, Germany. michael.gramlich@med.uni-tuebingen.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Gramlich
mesh_terms: D000818:Animals; D017209:Apoptosis; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D064211:Connectin / Q000235:genetics*; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism*
chemical_list: D064211:Connectin; C518820:IEX-1 protein, mouse; D017874:Immediate-Early Proteins
keywords: IER3; apoptosis; dilated cardiomyopathy; heart failure; mouse model; titin