title: Endothelin-1 regulates cardiac sympathetic innervation in the rodent heart by controlling nerve growth factor expression.
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, 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.
authors.affiliation: Cardiopulmonary Division, Department of Internal Medicine, Keio University School of Medicine, Tookyo, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Ieda
authors.forename: Keiichi
authors.initials: K
authors.lastname: Fukuda
authors.forename: Yasuyo
authors.initials: Y
authors.lastname: Hisaka
authors.forename: Kensuke
authors.initials: K
authors.lastname: Kimura
authors.forename: Haruko
authors.initials: H
authors.lastname: Kawaguchi
authors.forename: Jun
authors.initials: J
authors.lastname: Fujita
authors.forename: Kouji
authors.initials: K
authors.lastname: Shimoda
authors.forename: Eiko
authors.initials: E
authors.lastname: Takeshita
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Okano
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Kurihara
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kurihara
authors.forename: Junji
authors.initials: J
authors.lastname: Ishida
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Fukamizu
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Federoff
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ogawa
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D019332:Endothelin-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D006321:Heart / Q000294:innervation* / Q000502:physiology; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism; D020932:Nerve Growth Factor / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000196:embryology* / Q000378:metabolism
chemical_list: D019332:Endothelin-1; D020932:Nerve Growth Factor