AMP-activated protein kinase α1-sensitive activation of AP-1 in cardiomyocytes.
AMP-activated protein kinase (Ampk) regulates myocardial energy metabolism and plays a crucial role in the response to cell stress. In the failing heart, an isoform shift of the predominant Ampkα2 to the Ampkα1 was observed. The present study explored possible isoform specific effects of Ampkα1 in cardiomyocytes. To this end, experiments were performed in HL-1 cardiomyocytes, as well as in Ampkα1-deficient and corresponding wild-type mice and mice following AAV9-mediated cardiac overexpression of constitutively active Ampkα1. As a result, in HL-1 cardiomyocytes, overexpression of constitutively active Ampkα1 increased the phosphorylation of Pkcζ. Constitutively active Ampkα1 further increased AP-1-dependent transcriptional activity and mRNA expression of the AP-1 target genes c-Fos, Il6 and Ncx1, effects blunted by Pkcζ silencing. In HL-1 cardiomyocytes, angiotensin-II activated AP-1, an effect blunted by silencing of Ampkα1 and Pkcζ, but not of Ampkα2. In wild-type mice, angiotensin-II infusion increased cardiac Ampkα1 and cardiac Pkcζ protein levels, as well as c-Fos, Il6 and Ncx1 mRNA expression, effects blunted in Ampkα1-deficient mice. Pressure overload by transverse aortic constriction (TAC) similarly increased cardiac Ampkα1 and Pkcζ abundance as well as c-Fos, Il6 and Ncx1 mRNA expression, effects again blunted in Ampkα1-deficient mice. AAV9-mediated cardiac overexpression of constitutively active Ampkα1 increased Pkcζ protein abundance and the mRNA expression of c-Fos, Il6 and Ncx1 in cardiac tissue. In conclusion, Ampkα1 promotes myocardial AP-1 activation in a Pkcζ-dependent manner and thus contributes to cardiac stress signaling.
Department of Physiology & Cardiology and Cardiovascular Medicine, University of Tübingen, Gmelinstr.5/Otfried-Mueller-Str. 10, 72076, Tübingen, Germany.
Jakob
J
Voelkl
Department of Physiology & Cardiology and Cardiovascular Medicine, University of Tübingen, Gmelinstr.5/Otfried-Mueller-Str. 10, 72076, Tübingen, Germany.
Ioana
I
Alesutan
Department of Cardiology, Charité, Campus Virchow & German Centre for Cardiovascular Research (DZHK), Charite & Berlin Institute of Health, Augustenburger Platz 1, 13353 Berlin, Germany.
Uwe
U
Primessnig
Department of Physiology & Cardiology and Cardiovascular Medicine, University of Tübingen, Gmelinstr.5/Otfried-Mueller-Str. 10, 72076, Tübingen, Germany.
Martina
M
Feger
Department of Physiology & Cardiology and Cardiovascular Medicine, University of Tübingen, Gmelinstr.5/Otfried-Mueller-Str. 10, 72076, Tübingen, Germany.
Sobuj
S
Mia
Department of Internal Medicine III, University of Heidelberg, Im Neuenheimer Feld 410, Heidelberg, Germany, and DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany.
Andreas
A
Jungmann
Department of Physiology & Cardiology and Cardiovascular Medicine, University of Tübingen, Gmelinstr.5/Otfried-Mueller-Str. 10, 72076, Tübingen, Germany.
Tatsiana
T
Castor
Department of Physiology & Cardiology and Cardiovascular Medicine, University of Tübingen, Gmelinstr.5/Otfried-Mueller-Str. 10, 72076, Tübingen, Germany.
Robert
R
Viereck
Department of Medicine - Cardiology, University Hospital Bonn, Sigmund-Freud-Str.25, 53127 Bonn, Germany.
Florian
F
Stöckigt
Department of Physiology & Cardiology and Cardiovascular Medicine, University of Tübingen, Gmelinstr.5/Otfried-Mueller-Str. 10, 72076, Tübingen, Germany.
Oliver
O
Borst
Department of Physiology & Cardiology and Cardiovascular Medicine, University of Tübingen, Gmelinstr.5/Otfried-Mueller-Str. 10, 72076, Tübingen, Germany.
Meinrad
M
Gawaz
Department of Medicine - Cardiology, University Hospital Bonn, Sigmund-Freud-Str.25, 53127 Bonn, Germany.
Jan Wilko
JW
Schrickel
Department of Medicine - Cardiology, Medical University Innsbruck, Anichstr.35, 6020 Innsbruck, Austria.
Bernhard
B
Metzler
Department of Internal Medicine III, University of Heidelberg, Im Neuenheimer Feld 410, Heidelberg, Germany, and DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany.
Hugo A
HA
Katus
Department of Internal Medicine III, University of Heidelberg, Im Neuenheimer Feld 410, Heidelberg, Germany, and DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany.
Oliver J
OJ
Müller
Department of Cardiology, Charité, Campus Virchow & German Centre for Cardiovascular Research (DZHK), Charite & Berlin Institute of Health, Augustenburger Platz 1, 13353 Berlin, Germany; Department of Cardiology, University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria.
Burkert
B
Pieske
Department of Cardiology, Charité, Campus Virchow & German Centre for Cardiovascular Research (DZHK), Charite & Berlin Institute of Health, Augustenburger Platz 1, 13353 Berlin, Germany.
Frank R
FR
Heinzel
Department of Physiology & Cardiology and Cardiovascular Medicine, University of Tübingen, Gmelinstr.5/Otfried-Mueller-Str. 10, 72076, Tübingen, Germany. Electronic address: florian.lang@uni-tuebingen.de.
Florian
F
Lang
D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000229:Dependovirus / Q000235:genetics; D015870:Gene Expression; D005822:Genetic Vectors / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism*; D020033:Protein Isoforms; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014161:Transduction, Genetic
D020033:Protein Isoforms; D018808:Transcription Factor AP-1; D011493:Protein Kinase C; D055372:AMP-Activated Protein Kinases
AMP-activated protein kinase; AP-1 transcription factor (AP-1); Angiotensin-II; Cardiomyocytes; Heart failure; Protein kinase C (PKC)