Mechanistic role of the CREB-regulated transcription coactivator 1 in cardiac hypertrophy.

Details

Serval ID
serval:BIB_D25965B189D5
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Mechanistic role of the CREB-regulated transcription coactivator 1 in cardiac hypertrophy.
Journal
Journal of molecular and cellular cardiology
Author(s)
Morhenn K., Quentin T., Wichmann H., Steinmetz M., Prondzynski M., Söhren K.D., Christ T., Geertz B., Schröder S., Schöndube F.A., Hasenfuss G., Schlossarek S., Zimmermann W.H., Carrier L., Eschenhagen T., Cardinaux J.R., Lutz S., Oetjen E.
ISSN
1095-8584 (Electronic)
ISSN-L
0022-2828
Publication state
Published
Issued date
02/2019
Peer-reviewed
Oui
Volume
127
Pages
31-43
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
The sympathetic nervous system is the main stimulator of cardiac function. While acute activation of the β-adrenoceptors exerts positive inotropic and lusitropic effects by increasing cAMP and Ca <sup>2+</sup> , chronically enhanced sympathetic tone with changed β-adrenergic signaling leads to alterations of gene expression and remodeling. The CREB-regulated transcription coactivator 1 (CRTC1) is activated by cAMP and Ca <sup>2+</sup> . In the present study, the regulation of CRTC1 in cardiomyocytes and its effect on cardiac function and growth was investigated. In cardiomyocytes, isoprenaline induced dephosphorylation, and thus activation of CRTC1, which was prevented by propranolol. Crtc1-deficient mice exhibited left ventricular dysfunction, hypertrophy and enlarged cardiomyocytes. However, isoprenaline-induced contractility of isolated trabeculae or phosphorylation of cardiac troponin I, cardiac myosin-binding protein C, phospholamban, and ryanodine receptor were not altered, suggesting that cardiac dysfunction was due to the global lack of Crtc1. The mRNA and protein levels of the Gα <sub>q</sub> GTPase activating protein regulator of G-protein signaling 2 (RGS2) were lower in hearts of Crtc1-deficient mice. Chromatin immunoprecipitation and reporter gene assays showed stimulation of the Rgs2 promoter by CRTC1. In Crtc1-deficient cardiomyocytes, phosphorylation of the Gα <sub>q</sub> -downstream kinase ERK was enhanced. CRTC1 content was higher in cardiac tissue from patients with aortic stenosis or hypertrophic cardiomyopathy and from two murine models mimicking these diseases. These data suggest that increased CRTC1 in maladaptive hypertrophy presents a compensatory mechanism to delay disease progression in part by enhancing Rgs2 gene transcription. Furthermore, the present study demonstrates an important role of CRTC1 in the regulation of cardiac function and growth.
Keywords
Animals, Cardiomegaly/diagnostic imaging, Cardiomegaly/metabolism, Cardiomegaly/physiopathology, Cyclic AMP-Dependent Protein Kinases/metabolism, HEK293 Cells, Humans, Mice, Inbred C57BL, Myocytes, Cardiac/metabolism, Phosphorylation, Promoter Regions, Genetic, RGS Proteins/genetics, RGS Proteins/metabolism, RNA, Messenger/genetics, RNA, Messenger/metabolism, Rats, Wistar, Receptors, Adrenergic, beta/metabolism, Signal Transduction, Transcription Factors/deficiency, Transcription Factors/metabolism, CREB-regulated transcription coactivator 1, Hypertrophy, Regulator of G protein signaling 2, β-Adrenergic signaling
Pubmed
Web of science
Create date
13/12/2018 9:49
Last modification date
11/01/2020 6:16
Usage data