Development, maturation, and transdifferentiation of cardiac sympathetic nerves

Kensuke Kimura, Masaki Ieda, Keiichi Fukuda

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

The heart is electrically and mechanically controlled as a syncytium by the autonomic nervous system. The cardiac nervous system comprises the sympathetic, parasympathetic, and sensory nervous systems that together regulate heart function on demand. Sympathetic electric activation was initially considered the main regulator of cardiac function; however, modern molecular biotechnological approaches have provided a new dimension to our understanding of the mechanisms controlling the cardiac nervous system. The heart is extensively innervated, although the innervation density is not uniform within the heart, being high in the subepicardium and the special conduction system. We and others showed previously that the balance between neural chemoattractants and chemorepellents determine cardiac nervous development, with both factors expressed in heart. Nerve growth factor is a potent chemoattractant synthesized by cardiomyocytes, whereas Sema3a is a neural chemorepellent expressed specifically in the subendocardium. Disruption of this well-organized molecular balance and innervation density can induce sudden cardiac death due to lethal arrhythmias. In diseased hearts, various causes and mechanisms underlie cardiac sympathetic abnormalities, although their detailed pathology and significance remain contentious. We reported that cardiac sympathetic rejuvenation occurs in cardiac hypertrophy and, moreover, interleukin-6 cytokines secreted from the failing myocardium induce cholinergic transdifferentiation of the cardiac sympathetic system via a gp130 signaling pathway, affecting cardiac performance and prognosis. In this review, we summarize the molecular mechanisms involved in sympathetic development, maturation, and transdifferentiation, and propose their investigation as new therapeutic targets for heart disease.

Original languageEnglish
Pages (from-to)325-336
Number of pages12
JournalCirculation Research
Volume110
Issue number2
DOIs
Publication statusPublished - 2012 Jan 20

Fingerprint

Chemotactic Factors
Heart Diseases
Semaphorin-3A
Parasympathetic Nervous System
Rejuvenation
Autonomic Nervous System
Sudden Cardiac Death
Sympathetic Nervous System
Cardiomegaly
Nerve Growth Factor
Giant Cells
Cardiac Myocytes
Cholinergic Agents
Nervous System
Cardiac Arrhythmias
Interleukin-6
Myocardium
Pathology
Cytokines
Therapeutics

Keywords

  • cardiac innervation patterning
  • cardiac rejuvenation
  • cardiac sympathetic nervous system
  • cholinergic transdifferentiation
  • IL-6 cytokines
  • nerve growth factor

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Development, maturation, and transdifferentiation of cardiac sympathetic nerves. / Kimura, Kensuke; Ieda, Masaki; Fukuda, Keiichi.

In: Circulation Research, Vol. 110, No. 2, 20.01.2012, p. 325-336.

Research output: Contribution to journalArticle

Kimura, Kensuke ; Ieda, Masaki ; Fukuda, Keiichi. / Development, maturation, and transdifferentiation of cardiac sympathetic nerves. In: Circulation Research. 2012 ; Vol. 110, No. 2. pp. 325-336.
@article{0bc1f13c640a4580a6334e0c5ce1d5b5,
title = "Development, maturation, and transdifferentiation of cardiac sympathetic nerves",
abstract = "The heart is electrically and mechanically controlled as a syncytium by the autonomic nervous system. The cardiac nervous system comprises the sympathetic, parasympathetic, and sensory nervous systems that together regulate heart function on demand. Sympathetic electric activation was initially considered the main regulator of cardiac function; however, modern molecular biotechnological approaches have provided a new dimension to our understanding of the mechanisms controlling the cardiac nervous system. The heart is extensively innervated, although the innervation density is not uniform within the heart, being high in the subepicardium and the special conduction system. We and others showed previously that the balance between neural chemoattractants and chemorepellents determine cardiac nervous development, with both factors expressed in heart. Nerve growth factor is a potent chemoattractant synthesized by cardiomyocytes, whereas Sema3a is a neural chemorepellent expressed specifically in the subendocardium. Disruption of this well-organized molecular balance and innervation density can induce sudden cardiac death due to lethal arrhythmias. In diseased hearts, various causes and mechanisms underlie cardiac sympathetic abnormalities, although their detailed pathology and significance remain contentious. We reported that cardiac sympathetic rejuvenation occurs in cardiac hypertrophy and, moreover, interleukin-6 cytokines secreted from the failing myocardium induce cholinergic transdifferentiation of the cardiac sympathetic system via a gp130 signaling pathway, affecting cardiac performance and prognosis. In this review, we summarize the molecular mechanisms involved in sympathetic development, maturation, and transdifferentiation, and propose their investigation as new therapeutic targets for heart disease.",
keywords = "cardiac innervation patterning, cardiac rejuvenation, cardiac sympathetic nervous system, cholinergic transdifferentiation, IL-6 cytokines, nerve growth factor",
author = "Kensuke Kimura and Masaki Ieda and Keiichi Fukuda",
year = "2012",
month = "1",
day = "20",
doi = "10.1161/CIRCRESAHA.111.257253",
language = "English",
volume = "110",
pages = "325--336",
journal = "Circulation Research",
issn = "0009-7330",
publisher = "Lippincott Williams and Wilkins",
number = "2",

}

TY - JOUR

T1 - Development, maturation, and transdifferentiation of cardiac sympathetic nerves

AU - Kimura, Kensuke

AU - Ieda, Masaki

AU - Fukuda, Keiichi

PY - 2012/1/20

Y1 - 2012/1/20

N2 - The heart is electrically and mechanically controlled as a syncytium by the autonomic nervous system. The cardiac nervous system comprises the sympathetic, parasympathetic, and sensory nervous systems that together regulate heart function on demand. Sympathetic electric activation was initially considered the main regulator of cardiac function; however, modern molecular biotechnological approaches have provided a new dimension to our understanding of the mechanisms controlling the cardiac nervous system. The heart is extensively innervated, although the innervation density is not uniform within the heart, being high in the subepicardium and the special conduction system. We and others showed previously that the balance between neural chemoattractants and chemorepellents determine cardiac nervous development, with both factors expressed in heart. Nerve growth factor is a potent chemoattractant synthesized by cardiomyocytes, whereas Sema3a is a neural chemorepellent expressed specifically in the subendocardium. Disruption of this well-organized molecular balance and innervation density can induce sudden cardiac death due to lethal arrhythmias. In diseased hearts, various causes and mechanisms underlie cardiac sympathetic abnormalities, although their detailed pathology and significance remain contentious. We reported that cardiac sympathetic rejuvenation occurs in cardiac hypertrophy and, moreover, interleukin-6 cytokines secreted from the failing myocardium induce cholinergic transdifferentiation of the cardiac sympathetic system via a gp130 signaling pathway, affecting cardiac performance and prognosis. In this review, we summarize the molecular mechanisms involved in sympathetic development, maturation, and transdifferentiation, and propose their investigation as new therapeutic targets for heart disease.

AB - The heart is electrically and mechanically controlled as a syncytium by the autonomic nervous system. The cardiac nervous system comprises the sympathetic, parasympathetic, and sensory nervous systems that together regulate heart function on demand. Sympathetic electric activation was initially considered the main regulator of cardiac function; however, modern molecular biotechnological approaches have provided a new dimension to our understanding of the mechanisms controlling the cardiac nervous system. The heart is extensively innervated, although the innervation density is not uniform within the heart, being high in the subepicardium and the special conduction system. We and others showed previously that the balance between neural chemoattractants and chemorepellents determine cardiac nervous development, with both factors expressed in heart. Nerve growth factor is a potent chemoattractant synthesized by cardiomyocytes, whereas Sema3a is a neural chemorepellent expressed specifically in the subendocardium. Disruption of this well-organized molecular balance and innervation density can induce sudden cardiac death due to lethal arrhythmias. In diseased hearts, various causes and mechanisms underlie cardiac sympathetic abnormalities, although their detailed pathology and significance remain contentious. We reported that cardiac sympathetic rejuvenation occurs in cardiac hypertrophy and, moreover, interleukin-6 cytokines secreted from the failing myocardium induce cholinergic transdifferentiation of the cardiac sympathetic system via a gp130 signaling pathway, affecting cardiac performance and prognosis. In this review, we summarize the molecular mechanisms involved in sympathetic development, maturation, and transdifferentiation, and propose their investigation as new therapeutic targets for heart disease.

KW - cardiac innervation patterning

KW - cardiac rejuvenation

KW - cardiac sympathetic nervous system

KW - cholinergic transdifferentiation

KW - IL-6 cytokines

KW - nerve growth factor

UR - http://www.scopus.com/inward/record.url?scp=84856045096&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84856045096&partnerID=8YFLogxK

U2 - 10.1161/CIRCRESAHA.111.257253

DO - 10.1161/CIRCRESAHA.111.257253

M3 - Article

VL - 110

SP - 325

EP - 336

JO - Circulation Research

JF - Circulation Research

SN - 0009-7330

IS - 2

ER -