Regulation of cardiac gene expression by KLF15, a repressor of myocardin activity.
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.
Leenders
Joost J
JJ
Heart Failure Research Center, Academic Medical Center, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
Wijnen
Wino J
WJ
Heart Failure Research Center, Academic Medical Center, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
Hiller
Monika
M
Heart Failure Research Center, Academic Medical Center, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
van der Made
Ingeborg
I
Heart Failure Research Center, Academic Medical Center, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
Lentink
Viola
V
Experimental and Molecular Cardiology, Cardiovascular Research Institute Maastricht, University of Maastricht, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands.
van Leeuwen
Rick E W
REW
Experimental and Molecular Cardiology, Cardiovascular Research Institute Maastricht, University of Maastricht, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands.
Herias
Veronica
V
Experimental and Molecular Cardiology, Cardiovascular Research Institute Maastricht, University of Maastricht, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands.
Pokharel
Saraswati
S
Department of Pathology and Laboratory Medicine, University of Louisville, Louisville, Kentucky 40292.
Heymans
Stephane
S
Experimental and Molecular Cardiology, Cardiovascular Research Institute Maastricht, University of Maastricht, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands.
de Windt
Leon J
LJ
Experimental and Molecular Cardiology, Cardiovascular Research Institute Maastricht, University of Maastricht, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands.
Høydal
Morten A
MA
Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, NO-7491 Trondheim, Norway.
Pinto
Yigal M
YM
Heart Failure Research Center, Academic Medical Center, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
Creemers
Esther E
EE
Heart Failure Research Center, Academic Medical Center, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. Electronic address: e.e.creemers@amc.uva.nl.
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
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