TY - JOUR
T1 - Norepinephrine-induced nerve growth factor depletion causes cardiac sympathetic denervation in severe heart failure
AU - Kimura, Kensuke
AU - Kanazawa, Hideaki
AU - Ieda, Masaki
AU - Kawaguchi-Manabe, Haruko
AU - Miyake, Yoshiko
AU - Yagi, Takashi
AU - Arai, Takahide
AU - Sano, Motoaki
AU - Fukuda, Keiichi
N1 - Funding Information:
This study was supported in part by the research grants (10B-1) of “Nervous and Mental Disorders from the Ministry of Health and Welfare” and research grants from the Ministry of Education, Science and Culture, Japan, and Health Science Research Grants for Advanced Medical Technology from the Ministry of Welfare, Japan.
PY - 2010/8
Y1 - 2010/8
N2 - In severe congestive heart failure (CHF), sympathetic overactivity correlates with the exacerbation of cardiac performance. To test the hypothesis that the cardiac sympathetic nerve density dramatically changes with the acceleration of circulating norepinephrine (NE) concentration, we investigated the temporal association of nerve growth factor (NGF) expression in the heart and cardiac sympathetic nerve density during the development of CHF in the continuous NE-infused rats. The animals were analyzed at 0-, 1-, 3-, 7-, 14-, and 28-day after implantation of osmotic pump at a rate of 0.05. mg/kg/hr. The cardiac performance was temporally facilitated in NE-exposed rats at 3-day in accordance with the sympathetic hyper-innervation induced by the augmentation of NGF mRNA expression in the heart. In NE-treated rats, left ventricular end-diastolic pressure was significantly increased after 7-day and marked left ventricular hypertrophy and systemic fluid retention were observed at 28-day. CHF-induced sympathetic overactivity further increased plasma NE concentration in NE-treated rats and finally reached to 16.1 ± 5.6. ng/ml at 28-day (control level was 0.39 ± 0.1. ng/ml, p < 0.01). In the decompensated CHF rats at 28-day, the NGF mRNA expression was conspicuously reduced concomitant with the obvious nerve fiber loss confirmed by the immunostaining of nerve axonal marker, PGP9.5 and sympathetic neuron marker, tyrosine hydroxylase. This resulted in the attenuated tissue NE contents and the exacerbating cardiac performance. The cardiac sympathetic fiber loss was also confirmed in NE-exposed DBH (dopamine β-hydroxylase)-Cre/Floxed-EGFP (enhanced green fluorescent protein) mice with severe CHF, in which sympathetic nerve could be traced by EGFP. Our results suggest that the cardiac sympathetic nerve density is strictly regulated by the NGF expression in the heart and long-exposure of high plasma NE concentration caused myocardial NGF reduction, following sympathetic fiber loss in severe CHF animals.
AB - In severe congestive heart failure (CHF), sympathetic overactivity correlates with the exacerbation of cardiac performance. To test the hypothesis that the cardiac sympathetic nerve density dramatically changes with the acceleration of circulating norepinephrine (NE) concentration, we investigated the temporal association of nerve growth factor (NGF) expression in the heart and cardiac sympathetic nerve density during the development of CHF in the continuous NE-infused rats. The animals were analyzed at 0-, 1-, 3-, 7-, 14-, and 28-day after implantation of osmotic pump at a rate of 0.05. mg/kg/hr. The cardiac performance was temporally facilitated in NE-exposed rats at 3-day in accordance with the sympathetic hyper-innervation induced by the augmentation of NGF mRNA expression in the heart. In NE-treated rats, left ventricular end-diastolic pressure was significantly increased after 7-day and marked left ventricular hypertrophy and systemic fluid retention were observed at 28-day. CHF-induced sympathetic overactivity further increased plasma NE concentration in NE-treated rats and finally reached to 16.1 ± 5.6. ng/ml at 28-day (control level was 0.39 ± 0.1. ng/ml, p < 0.01). In the decompensated CHF rats at 28-day, the NGF mRNA expression was conspicuously reduced concomitant with the obvious nerve fiber loss confirmed by the immunostaining of nerve axonal marker, PGP9.5 and sympathetic neuron marker, tyrosine hydroxylase. This resulted in the attenuated tissue NE contents and the exacerbating cardiac performance. The cardiac sympathetic fiber loss was also confirmed in NE-exposed DBH (dopamine β-hydroxylase)-Cre/Floxed-EGFP (enhanced green fluorescent protein) mice with severe CHF, in which sympathetic nerve could be traced by EGFP. Our results suggest that the cardiac sympathetic nerve density is strictly regulated by the NGF expression in the heart and long-exposure of high plasma NE concentration caused myocardial NGF reduction, following sympathetic fiber loss in severe CHF animals.
KW - Congestive heart failure
KW - Nerve growth factor
KW - Norepinephrine
KW - Sympathetic denervation
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U2 - 10.1016/j.autneu.2010.02.005
DO - 10.1016/j.autneu.2010.02.005
M3 - Article
C2 - 20335077
AN - SCOPUS:77955271874
SN - 1566-0702
VL - 156
SP - 27
EP - 35
JO - Autonomic Neuroscience: Basic and Clinical
JF - Autonomic Neuroscience: Basic and Clinical
IS - 1-2
ER -