Endothelin-1 regulates cardiac sympathetic innervation in the rodent heart by controlling nerve growth factor expression
Endothelin-1 regulates cardiac sympathetic innervation in the rodent heart by controlling nerve growth factor expression
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DOI：
10.1172/jci200419480
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发表时间：
2004-03-01
影响因子：
15.9
通讯作者：
Ogawa, S
中科院分区：
文献类型：
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作者：
Ieda, M;Fukuda, K;Ogawa, S
心脏交感神经在调节心脏功能中发挥着重要作用，神经生长因子（NGF）有助于其发育和维持。然而，人们对调节 NGF 表达和心脏交感神经支配的分子机制知之甚少。为了鉴定心肌细胞中 NGF 的调节因子，我们发现内皮素-1 特异性上调原代培养的心肌细胞中的 NGF 表达。内皮素 1 诱导的 NGF 增强是由内皮素 A 受体、Gibetagamma、PKC、Src 家族、EGFR、细胞外信号调节激酶、p38MAPK、激活蛋白 1 和 CCAAT/增强子结合蛋白 δ 元件介导的。条件培养基或与内皮素-l刺激的心肌细胞共培养引起NGF介导的PC12细胞分化。 NGF 表达、心脏交感神经支配和去甲肾上腺素浓度在内皮素-1 缺乏的小鼠心脏中明显降低，但在血管紧张素原缺乏的小鼠中则没有。在内皮素-l缺乏的小鼠中，交感星状神经节表现出过度的细胞凋亡，并在胚胎晚期表现出神经元的损失。此外，在内皮素-1缺陷小鼠中，心脏特异性NGF过度表达克服了交感神经支配减少和星状神经节神经元损失的问题。这些发现表明内皮素-1 调节心肌细胞中 NGF 的表达，并在心脏的交感神经支配中发挥关键作用。
The cardiac sympathetic nerve plays an important role in regulating cardiac function, and nerve growth factor (NGF) contributes to its development and maintenance. However, little is known about the molecular mechanisms that regulate NGF expression and sympathetic innervation of the heart. In an effort to identify regulators of NGF in cardiomyocytes, we found that endothelin-1 specifically upregulated NGF expression in primary cultured carctiomyocytes. Endothelin-1-induced NGF augmentation was mediated by the endothelin-A receptor, Gibetagamma, PKC, the Src family, EGFR, extracellular signal-regulated kinase, p38MAPK, activator protein-1, and the CCAAT/enhancer-binding protein delta element. Either conditioned medium or coculture with endothelin-l-stimulated cardiomyocytes caused NGF-mediated PC12 cell differentiation. NGF expression, cardiac sympathetic innervation, and norepinephrine concentration were specifically reduced in endothelin-1-deficient mouse hearts, but not in angiotensinogen-deficient mice. In endothelin-l-deficient mice the sympathetic stellate ganglia exhibited excess apoptosis and displayed loss of neurons at the late embryonic stage. Furthermore, cardiac-specific overexpression of NGF in endothelin-1-deficient mice overcame the reduced sympathetic innervation and loss of stellate ganglia neurons. These findings indicate that endothelin-1 regulates NGF expression in cardiomyocytes and plays a critical role in sympathetic innervation of the heart.