Department of Regenerative Medicine and Advanced Cardiac Therapeutics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Auton Neurosci. 2010 Aug 25;156(1-2):27-35. doi: 10.1016/j.autneu.2010.02.005. Epub 2010 Mar 23.
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 beta-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.
在严重充血性心力衰竭（CHF）中，交感神经过度活跃与心脏功能恶化相关。为了验证以下假设，即心脏交感神经密度会随着循环去甲肾上腺素（NE）浓度的加速而显著变化，我们研究了在连续 NE 输注大鼠 CHF 发展过程中心脏神经生长因子（NGF）表达与心脏交感神经密度的时间关联。动物在植入渗透泵后的 0、1、3、7、14 和 28 天进行分析，泵的输注速率为 0.05mg/kg/hr。在 NE 暴露的大鼠中，在第 3 天心脏性能得到了暂时的改善，这与心脏中 NGF mRNA 表达的增加引起的交感神经过度支配相一致。在 NE 处理的大鼠中，左心室舒张末期压在第 7 天显著升高，并且在第 28 天观察到明显的左心室肥厚和全身液体潴留。CHF 引起的交感神经过度活跃进一步增加了 NE 处理大鼠的血浆 NE 浓度，最终在第 28 天达到 16.1+/-5.6ng/ml（对照水平为 0.39+/-0.1ng/ml，p<0.01）。在第 28 天失代偿性 CHF 大鼠中，NGF mRNA 表达明显降低，同时通过神经轴突标志物 PGP9.5 和酪氨酸羟化酶的免疫染色证实了明显的神经纤维丢失。这导致组织 NE 含量降低和心脏功能恶化。在严重 CHF 的 NE 暴露 DBH（多巴胺β-羟化酶）-Cre/Floxed-EGFP（增强型绿色荧光蛋白）小鼠中也证实了心脏交感神经纤维丢失，其中可以通过 EGFP 追踪到交感神经。我们的结果表明，心脏交感神经密度受到心脏中 NGF 表达的严格调节，而长期高血浆 NE 浓度暴露导致心肌 NGF 减少，随后在严重 CHF 动物中出现交感神经纤维丢失。
