title: Regulation of nerve growth factor in the heart: the role of the calcineurin-NFAT pathway.
abstract: A heightened sympathetic tone accelerates the development of lethal arrhythmias after myocardial infarction (MI) and the progression of heart failure (HF). Cardiomyocytes control their local neural milieu by expression of nerve growth factor (NGF), which triggers sympathetic neural growth (sympathetic nerve sprouting: SNS). The molecular mechanisms that regulate NGF expression are largely unknown. During HF or MI the myocytes are exposed to increased mechanical load and adrenergic stimulation. Both stimuli induce myocyte hypertrophy. The angiotensin-II-calcineurin-NFAT (nuclear factor of activated t-cells) pathway is a well characterized signaling cascade in the pathogenesis of myocyte hypertrophy. The present study aims to investigate the molecular mechanisms by which mechanical stretch and/or alpha-1-adrenergic stimulation affect NGF expression in neonatal rat ventricular myocytes. Both stimuli resulted in a down-regulation of NGF gene and protein expression. Angiotensin-II type 1 receptor blockade with losartan blunted the stretch-induced NGF down-regulation. Specific calcineurin inhibition with cyclosporine A and FK506 or NFAT inhibition with 11R-VIVIT reversed the stretch or alpha-1-adrenergic induced decrease of NGF. Calcineurin over-expression increased NFAT-DNA binding activity and decreased NGF expression. The magnitude of NGF decrease was sufficient to reduce neurite outgrowth of cultured sympathetic neurons. In conclusion, mechanical stretch and alpha-1-adrenergic stimulation contribute to a decrease of cardiomyocyte NGF expression via the calcineurin-NFAT pathway. To evaluate if the calcineurin-NFAT is critically involved in the pathogenesis of SNS further in-vivo studies in models of HF and MI are required. Nevertheless, the calcineurin-NFAT pathway may provide promising starting points for new pharmacological strategies to prevent SNS in the heart.
authors.affiliation: Department of Cardiology, Angiology and Pulmonology, Medical Faculty, RWTH Aachen University, Pauwelsstr. 30, D-52074 Aachen, Germany.
authors.forename: Obaida R
authors.initials: OR
authors.lastname: Rana
authors.forename: Erol
authors.initials: E
authors.lastname: Saygili
authors.forename: Christian
authors.initials: C
authors.lastname: Meyer
authors.forename: Christopher
authors.initials: C
authors.lastname: Gemein
authors.forename: Alexander
authors.initials: A
authors.lastname: Krüttgen
authors.forename: Michael G
authors.initials: MG
authors.lastname: Andrzejewski
authors.forename: Andreas
authors.initials: A
authors.lastname: Ludwig
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schotten
authors.forename: Robert H G
authors.initials: RH
authors.lastname: Schwinger
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
authors.forename: Joachim
authors.initials: J
authors.lastname: Weis
authors.forename: Karl
authors.initials: K
authors.lastname: Mischke
authors.forename: Tienush
authors.initials: T
authors.lastname: Rassaf
authors.forename: Malte
authors.initials: M
authors.lastname: Kelm
authors.forename: Patrick
authors.initials: P
authors.lastname: Schauerte
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019703:Calcineurin / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D009928:Organ Specificity / Q000187:drug effects; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D013314:Stress, Mechanical; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000378:metabolism; D014162:Transfection
chemical_list: D050778:NFATC Transcription Factors; D044140:Receptor, Angiotensin, Type 1; D018340:Receptors, Adrenergic, alpha-1; D010656:Phenylephrine; D020932:Nerve Growth Factor; D019703:Calcineurin