Characterization of the regulatory mechanisms of activating transcription factor 3 by hypertrophic stimuli in rat cardiomyocytes
| Autor: | Harri Pennanen, Hanna Säkkinen, Heikki Ruskoaho, Elina Koivisto, Jaana Rysä, Jani Aro, Alicia Jurado Acosta, Leena Kaikkonen, Anne-Mari Moilanen, Heikki Tokola |
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| Přispěvatelé: | Faculty of Pharmacy, Division of Pharmacology and Pharmacotherapy |
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Male
MAPK/ERK pathway Cell signaling Activating transcription factor Signal transduction ERK signaling cascade p38 Mitogen-Activated Protein Kinases GATA-4 DISEASE Rats Sprague-Dawley Gene expression Medicine and Health Sciences Myocytes Cardiac Cells Cultured Multidisciplinary Endothelin-1 NF-kappa B Signaling cascades PKA signaling cascade Biomechanical Phenomena APOPTOSIS Isoenzymes 317 Pharmacy Homeobox Protein Nkx-2.5 HEART-FAILURE Medicine Female Inflammation Mediators Immediate early gene Protein Binding Research Article Transcriptional Activation Cell biology MAPK signaling cascades ATF3 GENE-EXPRESSION Science education Cardiology Biology Cardiovascular Pharmacology Plasminogen Activator Inhibitor 1 Animals Protein kinase A Protein Kinase Inhibitors Transcription factor Homeodomain Proteins Heart Failure Pharmacology ATF3 Activating Transcription Factor 3 Biology and life sciences INDUCED CARDIAC-HYPERTROPHY PATHWAYS Cardiomyopathy Hypertrophic PROTEIN-KINASE NFKB1 Molecular biology VASCULAR ENDOTHELIAL-CELLS ALPHA Transcription Factors |
| Zdroj: | PLoS ONE, Vol 9, Iss 8, p e105168 (2014) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | AimsActivating transcription factor 3 (ATF3) is a stress-activated immediate early gene suggested to have both detrimental and cardioprotective role in the heart. Here we studied the mechanisms of ATF3 activation by hypertrophic stimuli and ATF3 downstream targets in rat cardiomyocytes.Methods and resultsWhen neonatal rat cardiomyocytes were exposed to endothelin-1 (ET-1, 100 nM) and mechanical stretching in vitro, maximal increase in ATF3 expression occurred at 1 hour. Inhibition of extracellular signal-regulated kinase (ERK) by PD98059 decreased ET-1- and stretch-induced increase of ATF3 protein but not ATF3 mRNA levels, whereas protein kinase A (PKA) inhibitor H89 attenuated both ATF3 mRNA transcription and protein expression in response to ET-1 and stretch. To characterize further the regulatory mechanisms upstream of ATF3, p38 mitogen-activated protein kinase (MAPK) signaling was investigated using a gain-of-function approach. Adenoviral overexpression of p38α, but not p38β, increased ATF3 mRNA and protein levels as well as DNA binding activity. To investigate the role of ATF3 in hypertrophic process, we overexpressed ATF3 by adenovirus-mediated gene transfer. In vitro, ATF3 gene delivery attenuated the mRNA transcription of interleukin-6 (IL-6) and plasminogen activator inhibitor-1 (PAI-1), and enhanced nuclear factor-κB (NF-κB) and Nkx-2.5 DNA binding activities. Reduced PAI-1 expression was also detected in vivo in adult rat heart by direct intramyocardial adenovirus-mediated ATF3 gene delivery.ConclusionsThese data demonstrate that ATF3 activation by ET-1 and mechanical stretch is partly mediated through ERK and cAMP-PKA pathways, whereas p38 MAPK pathway is involved in ATF3 activation exclusively through p38α isoform. ATF3 activation caused induction of modulators of the inflammatory response NF-κB and Nkx-2.5, as well as attenuation of pro-fibrotic and pro-inflammatory proteins IL-6 and PAI-1, suggesting cardioprotective role for ATF3 in the heart. |
| Databáze: | OpenAIRE |
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