title: Regulation of cardiac gene expression by KLF15, a repressor of myocardin activity.
abstract: Pathological forms of left ventricular hypertrophy (LVH) often progress to heart failure. Specific transcription factors have been identified that activate the gene program to induce pathological forms of LVH. It is likely that apart from activating transcriptional inducers of LVH, constitutive transcriptional repressors need to be removed during the development of cardiac hypertrophy. Here, we report that the constitutive presence of Krüppel-like factor 15 (KLF15) is lost in pathological hypertrophy and that this loss precedes progression toward heart failure. We show that transforming growth factor-beta-mediated activation of p38 MAPK is necessary and sufficient to decrease KLF15 expression. We further show that KLF15 robustly inhibits myocardin, a potent transcriptional activator. Loss of KLF15 during pathological LVH relieves the inhibitory effects on myocardin and stimulates the expression of serum response factor target genes, such as atrial natriuretic factor. This uncovers a novel mechanism where activated p38 MAPK decreases KLF15, an important constitutive transcriptional repressor whose removal seems a vital step to allow the induction of pathological LVH.
authors.affiliation: Heart Failure Research Center, Academic Medical Center, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Joost J
authors.initials: JJ
authors.lastname: Leenders
authors.affiliation: Heart Failure Research Center, Academic Medical Center, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Wino J
authors.initials: WJ
authors.lastname: Wijnen
authors.affiliation: Heart Failure Research Center, Academic Medical Center, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Monika
authors.initials: M
authors.lastname: Hiller
authors.affiliation: Heart Failure Research Center, Academic Medical Center, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Ingeborg
authors.initials: I
authors.lastname: van der Made
authors.affiliation: Experimental and Molecular Cardiology, Cardiovascular Research Institute Maastricht, University of Maastricht, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands.
authors.forename: Viola
authors.initials: V
authors.lastname: Lentink
authors.affiliation: Experimental and Molecular Cardiology, Cardiovascular Research Institute Maastricht, University of Maastricht, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands.
authors.forename: Rick E W
authors.initials: REW
authors.lastname: van Leeuwen
authors.affiliation: Experimental and Molecular Cardiology, Cardiovascular Research Institute Maastricht, University of Maastricht, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands.
authors.forename: Veronica
authors.initials: V
authors.lastname: Herias
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Louisville, Louisville, Kentucky 40292.
authors.forename: Saraswati
authors.initials: S
authors.lastname: Pokharel
authors.affiliation: Experimental and Molecular Cardiology, Cardiovascular Research Institute Maastricht, University of Maastricht, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands.
authors.forename: Stephane
authors.initials: S
authors.lastname: Heymans
authors.affiliation: Experimental and Molecular Cardiology, Cardiovascular Research Institute Maastricht, University of Maastricht, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands.
authors.forename: Leon J
authors.initials: LJ
authors.lastname: de Windt
authors.affiliation: Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, NO-7491 Trondheim, Norway.
authors.forename: Morten A
authors.initials: MA
authors.lastname: Høydal
authors.affiliation: Heart Failure Research Center, Academic Medical Center, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Yigal M
authors.initials: YM
authors.lastname: Pinto
authors.affiliation: Heart Failure Research Center, Academic Medical Center, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. Electronic address: e.e.creemers@amc.uva.nl.
authors.forename: Esther E
authors.initials: EE
authors.lastname: Creemers
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D051379:Mice; D009206:Myocardium / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D051381:Rats; D011917:Rats, Inbred Lew; D012097:Repressor Proteins / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099251:Myocardin
chemical_list: D009320:Atrial Natriuretic Factor; D004268:DNA-Binding Proteins; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D048051:p38 Mitogen-Activated Protein Kinases; D000099251:Myocardin; C467418:Klf15 protein, mouse; C520013:Klf15 protein, rat