Endothelin-1 regulates cardiac sympathetic innervation in the rodent heart by controlling nerve growth factor expression

Masaki Ieda, Keiichi Fukuda, Yasuyo Hisaka, Kensuke Kimura, Haruko Kawaguchi, Jun Fujita, Kouji Shimoda, Eiko Takeshita, Hideyuki Okano, Yukiko Kurihara, Hiroki Kurihara, Junji Ishida, Akiyoshi Fukamizu, Howard J. Federoff, Satoshi Ogawa

Research output: Contribution to journalArticle

88 Citations (Scopus)

Abstract

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, Giβγ, PKC, the Src family, EGFR, extracellular signal-regulated kinase, p38MAPK, activator protein-1, and the CCAAT/enhancer-binding protein δ 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.

Original languageEnglish
Pages (from-to)876-884
Number of pages9
JournalJournal of Clinical Investigation
Volume113
Issue number6
DOIs
Publication statusPublished - 2004 Mar

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Endothelin-1
Nerve Growth Factor
Rodentia
Cardiac Myocytes
Stellate Ganglion
CCAAT-Enhancer-Binding Proteins
Neurons
Endothelin A Receptors
Angiotensinogen
Sympathetic Ganglia
PC12 Cells
Extracellular Signal-Regulated MAP Kinases
Transcription Factor AP-1
Conditioned Culture Medium
Coculture Techniques
Cell Differentiation
Norepinephrine
Maintenance
Apoptosis

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Endothelin-1 regulates cardiac sympathetic innervation in the rodent heart by controlling nerve growth factor expression. / Ieda, Masaki; Fukuda, Keiichi; Hisaka, Yasuyo; Kimura, Kensuke; Kawaguchi, Haruko; Fujita, Jun; Shimoda, Kouji; Takeshita, Eiko; Okano, Hideyuki; Kurihara, Yukiko; Kurihara, Hiroki; Ishida, Junji; Fukamizu, Akiyoshi; Federoff, Howard J.; Ogawa, Satoshi.

In: Journal of Clinical Investigation, Vol. 113, No. 6, 03.2004, p. 876-884.

Research output: Contribution to journalArticle

Ieda, M, Fukuda, K, Hisaka, Y, Kimura, K, Kawaguchi, H, Fujita, J, Shimoda, K, Takeshita, E, Okano, H, Kurihara, Y, Kurihara, H, Ishida, J, Fukamizu, A, Federoff, HJ & Ogawa, S 2004, 'Endothelin-1 regulates cardiac sympathetic innervation in the rodent heart by controlling nerve growth factor expression', Journal of Clinical Investigation, vol. 113, no. 6, pp. 876-884. https://doi.org/10.1172/JCI200419480
Ieda, Masaki ; Fukuda, Keiichi ; Hisaka, Yasuyo ; Kimura, Kensuke ; Kawaguchi, Haruko ; Fujita, Jun ; Shimoda, Kouji ; Takeshita, Eiko ; Okano, Hideyuki ; Kurihara, Yukiko ; Kurihara, Hiroki ; Ishida, Junji ; Fukamizu, Akiyoshi ; Federoff, Howard J. ; Ogawa, Satoshi. / Endothelin-1 regulates cardiac sympathetic innervation in the rodent heart by controlling nerve growth factor expression. In: Journal of Clinical Investigation. 2004 ; Vol. 113, No. 6. pp. 876-884.
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