Critical role of transcription factor cyclic AMP response element modulator in beta1-adrenoceptor-mediated cardiac dysfunction.
BACKGROUND
Chronic stimulation of the beta(1)-adrenoceptor (beta(1)AR) plays a crucial role in the pathogenesis of heart failure; however, underlying mechanisms remain to be elucidated. The regulation by transcription factors cAMP response element-binding protein (CREB) and cyclic AMP response element modulator (CREM) represents a fundamental mechanism of cyclic AMP-dependent gene control possibly implicated in beta(1)AR-mediated cardiac deterioration.


RESULTS
We studied the role of CREM in beta(1)AR-mediated cardiac effects, comparing transgenic mice with heart-directed expression of beta(1)AR in the absence and presence of functional CREM. CREM inactivation protected from cardiomyocyte hypertrophy, fibrosis, and left ventricular dysfunction in beta(1)AR-overexpressing mice. Transcriptome and proteome analysis revealed a set of predicted CREB/CREM target genes including the cardiac ryanodine receptor, tropomyosin 1alpha, and cardiac alpha-actin as altered on the mRNA or protein level along with the improved phenotype in CREM-deficient beta(1)AR-transgenic hearts.


CONCLUSIONS
The results imply the regulation of genes by CREM as an important mechanism of beta(1)AR-induced cardiac damage in mice.
Lewin
Geertje
G
Institute of Pharmacology and Toxicology, University of Münster, Münster, Germany.
Matus
Marek
M
Basu
Abhijit
A
Frebel
Karin
K
Rohsbach
Sebastian Pius
SP
Safronenko
Andrej
A
Seidl
Matthias Dodo
MD
Stümpel
Frank
F
Buchwalow
Igor
I
König
Simone
S
Engelhardt
Stefan
S
Lohse
Martin J
MJ
Schmitz
Wilhelm
W
Müller
Frank Ulrich
FU
D000818:Animals; D006332:Cardiomegaly / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D000242:Cyclic AMP / Q000378:metabolism; D051786:Cyclic AMP Response Element Modulator / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D015180:Electrophoresis, Gel, Two-Dimensional; D020869:Gene Expression Profiling; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D040901:Proteomics; D012333:RNA, Messenger / Q000378:metabolism; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics / Q000378:metabolism*; D016277:Ventricular Function, Left / Q000502:physiology
C497411:Crem protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D012333:RNA, Messenger; D018342:Receptors, Adrenergic, beta-1; D051786:Cyclic AMP Response Element Modulator; D000242:Cyclic AMP