Activation and inactivation of cAMP-response element-mediated gene transcription in cardiac myocytes
| Autor: | Joachim Neumann, Bettina Linck, Jörg Knapp, Wilhelm Schmitz, Frank U. Müller, Peter Boknik, Hartmut Lüss |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
Cardiotonic Agents
Time Factors Transcription Genetic Physiology Response element Gene Expression Cell Cycle Proteins Chick Embryo Biology CREB Adenylyl cyclase Propane chemistry.chemical_compound 1-Methyl-3-isobutylxanthine Physiology (medical) Gene expression Cyclic AMP Phosphoprotein Phosphatases Animals Enzyme Inhibitors Phosphorylation Cyclic AMP Response Element-Binding Protein Luciferases Cells Cultured Plant Proteins Heart Failure Regulation of gene expression Forskolin Dose-Response Relationship Drug Activator (genetics) Myocardium Colforsin Isoproterenol Molecular biology Stimulation Chemical Enzyme Activation chemistry Ethanolamines Cantharidin biology.protein Cardiology and Cardiovascular Medicine Adenylyl Cyclases |
| Zdroj: | Cardiovascular Research. 52:95-102 |
| ISSN: | 0008-6363 |
| DOI: | 10.1016/s0008-6363(01)00361-3 |
| Popis: | Objective: Chronic β-adrenergic stimulation of the cAMP-dependent signalling pathway is implicated in functionally relevant expressional changes in congestive heart failure. We studied activation and inactivation of the cardiac gene transcription mediated by the cAMP-response element (CRE) and the CRE-binding protein (CREB) as an important mechanism of a cAMP-dependent gene regulation. Methods: We investigated the transcriptional activation by forskolin, an activator of the adenylyl cyclase, in chick embryonic cardiomyocytes transfected with a CRE-controlled luciferase construct in comparison to the phosphorylation and expression of CREB determined on immunoblots. Results: Forskolin (10 μmol/l; 8 h) increased CRE-mediated transcription and phosphorylation of CREB 13- and 1.5-fold, respectively. The phosphorylation was further elevated in combination with cantharidin, an inhibitor of type 1+2A protein phosphatases. The transcriptional response to forskolin was desensitized by pretreatment with forskolin (1 μmol/l; 24 h) while CREB phosphorylation was increased. In forskolin-pretreated cells, total CREB protein levels were decreased. Cantharidin did not restore the attenuated transcriptional response. Conclusions: In cardiomyocytes, there is an activation of the CRE-mediated gene transcription by forskolin that is attenuated after prolonged stimulation, and this attenuation is not dependent from a dephosphorylation of CREB. We suggest that attenuation of the CRE-mediated transcription through chronic stimulation of the cAMP-pathway, e.g. by elevated catecholamines, contributes to the altered expressional regulation in congestive heart failure. |
| Databáze: | OpenAIRE |
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