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/jci19480
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发表时间：
2004-03
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通讯作者：
M. Ieda;K. Fukuda;Yasuyo Hisaka;Kensuke Kimura;Haruko Kawaguchi;J. Fujita;K. Shimoda;Eiko Takeshita;H. Okano;Y. Kurihara;H. Kurihara;J. Ishida;A. Fukamizu;H. Federoff;S. Ogawa
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作者：
M. Ieda;K. Fukuda;Yasuyo Hisaka;Kensuke Kimura;Haruko Kawaguchi;J. Fujita;K. Shimoda;Eiko Takeshita;H. Okano;Y. Kurihara;H. Kurihara;J. Ishida;A. Fukamizu;H. Federoff;S. Ogawa
心交感神经在调节心功能中起重要作用，神经生长因子（NGF）参与其发育和维持。然而，关于调节NGF表达和心脏交感神经支配的分子机制知之甚少。为了确定心肌细胞中NGF的调节因子，我们发现内皮素-1在原代培养的心肌细胞中特异性上调NGF的表达。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-1刺激的心肌细胞共培养均可引起ngf介导的PC12细胞分化。内皮素-1缺陷小鼠的NGF表达、心脏交感神经支配和去甲肾上腺素浓度特异性降低，而血管紧张素原缺陷小鼠则无此现象。内皮素-1缺失小鼠交感星状神经节在胚胎后期出现过度凋亡和神经元丢失。此外，内皮素-1缺陷小鼠的心脏特异性过表达NGF克服了交感神经支配的减少和星状神经节神经元的丢失。这些发现表明，内皮素-1调节心肌细胞中NGF的表达，并在心脏交感神经支配中起关键作用。
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 cardiomyocytes. 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-1-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-1-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.