title: Rate and irregularity of electrical activation during atrial fibrillation affect myocardial NGF expression via different signalling routes.
abstract: An irregular ventricular response during atrial fibrillation (AF) has been shown to mediate an increase in sympathetic nerve activity in human subjects. The molecular mechanisms remain unclear. This study aimed to investigate the impact of rate and irregularity on nerve growth factor (NGF) expression in cardiomyocytes, since NGF is known to be the main contributor to cardiac sympathetic innervation density. Cell cultures of neonatal rat ventricular myocytes were electrically stimulated for 48 h with increasing rates (0, 5 and 50 Hz) and irregularity (standard deviation (SD)=5%, 25% and 50% of mean cycle length). Furthermore, we analyzed the calcineurin-NFAT and the endothelin-1 signalling pathways as possible contributors to NGF regulation during arrhythmic stimulation. We found that the increase of NGF expression reached its maximum at the irregularity of 25% SD by 5 Hz (NGF: 5 Hz 0% SD=1 vs. 5Hz 25% SD=1.57, P<0.05). Specific blockade of the ET-A receptor by BQ123 could abolish this NGF increase (NGF: 5 Hz 25% SD+BQ123=0.66, P<0.05). High frequency electrical field stimulation (HFES) with 50 Hz decreased the NGF expression in a significant manner (NGF: 50Hz=0.55, P<0.05). Inhibition of calcineurin-NFAT signalling with cyclosporine-A or 11R-VIVIT abolished the HFES induced NGF down-regulation (NGF: 50 Hz+CsA=1.14, P<0.05). In summary, this study reveals different signalling routes of NGF expression in cardiomyocytes exposed to increasing rates and irregularity. Whether this translates into different degrees of NGF expression and possibly neural sympathetic growth in various forms of ventricular rate control during AF remains to be elucidated in further studies.
authors: Department of Cardiology, University RWTH Aachen, Aachen, Germany. esaygili@ukaachen.de
authors: Erol
authors: E
authors: Saygili
authors: Obaida R
authors: OR
authors: Rana
authors: Claudia
authors: C
authors: Günzel
authors: Gediminas
authors: G
authors: Rackauskas
authors: Esra
authors: E
authors: Saygili
authors: Fawad
authors: F
authors: Noor-Ebad
authors: Christopher
authors: C
authors: Gemein
authors: Matthias D
authors: MD
authors: Zink
authors: Robert H G
authors: RH
authors: Schwinger
authors: Karl
authors: K
authors: Mischke
authors: Joachim
authors: J
authors: Weis
authors: Nikolaus
authors: N
authors: Marx
authors: Patrick
authors: P
authors: Schauerte
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000378:metabolism / Q000503:physiopathology*; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D019703:Calcineurin / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000737:chemistry; D004558:Electric Stimulation; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism; D005786:Gene Expression Regulation; D006352:Heart Ventricles / Q000166:cytology*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000378:metabolism; D020932:Nerve Growth Factor / Q000235:genetics* / Q000378:metabolism; D016501:Neurites / Q000502:physiology; D010456:Peptides, Cyclic / Q000494:pharmacology; D061251:Primary Cell Culture; D051381:Rats; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D017077:Culture Media, Conditioned; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D050778:NFATC Transcription Factors; D010456:Peptides, Cyclic; D009320:Atrial Natriuretic Factor; D020932:Nerve Growth Factor; D019703:Calcineurin; C072247:cyclo(Trp-Asp-Pro-Val-Leu)