Cardiac sympathetic rejuvenation: A link between nerve function and cardiac hypertrophy

Kensuke Kimura, Masaki Ieda, Hideaki Kanazawa, Takashi Yagi, Makoto Tsunoda, Shin Ichi Ninomiya, Hiroyuki Kurosawa, Kenji Yoshimi, Hideki Mochizuki, Kazuto Yamazaki, Satoshi Ogawa, Keiichi Fukuda

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Abstract

Neuronal function and innervation density is regulated by target organ-derived neurotrophic factors. Although cardiac hypertrophy drastically alternates the expression of various growth factors such as endothelin-1, angiotensin II, and leukemia inhibitory factor, little is known about nerve growth factor expression and its effect on the cardiac sympathetic nerves. This study investigated the impact of pressure overload-induced cardiac hypertrophy on the innervation density and cellular function of cardiac sympathetic nerves, including kinetics of norepinephrine synthesis and reuptake, and neuronal gene expression. Right ventricular hypertrophy was induced by monocrotaline treatment in Wistar rats. Newly developed cardiac sympathetic nerves expressing β3-tubulin (axonal marker), GAP43 (growth-associated cone marker), and tyrosine hydroxylase were markedly increased only in the right ventricle, in parallel with nerve growth factor upregulation. However, norepinephrine and dopamine content was paradoxically attenuated, and the protein and kinase activity of tyrosine hydroxylase were markedly downregulated in the right ventricle. The reuptake of [I]-metaiodobenzylguanidine and [H]-norepinephrine were also significantly diminished in the right ventricle, indicating functional downregulation in cardiac sympathetic nerves. Interestingly, we found cardiac sympathetic nerves in hypertrophic right ventricles strongly expressed highly polysialylated neural cell adhesion molecule (PSA-NCAM) (an immature neuron marker) as well as neonatal heart. Taken together, pressure overload induced anatomical sympathetic hyperinnervation but simultaneously caused deterioration of neuronal cellular function. This phenomenon was explained by the rejuvenation of cardiac sympathetic nerves as well as the hypertrophic cardiomyocytes, which also showed the fetal form gene expression.

Original languageEnglish
Pages (from-to)1755-1764
Number of pages10
JournalCirculation research
Volume100
Issue number12
DOIs
Publication statusPublished - 2007 Jun 1

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Keywords

  • Norepinephrine
  • Pulmonary hypertension
  • Rejuvenation
  • Sympathetic nervous system

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Kimura, K., Ieda, M., Kanazawa, H., Yagi, T., Tsunoda, M., Ninomiya, S. I., Kurosawa, H., Yoshimi, K., Mochizuki, H., Yamazaki, K., Ogawa, S., & Fukuda, K. (2007). Cardiac sympathetic rejuvenation: A link between nerve function and cardiac hypertrophy. Circulation research, 100(12), 1755-1764. https://doi.org/10.1161/01.RES.0000269828.62250.ab