A novel cardiac hypertrophic factor, neurotrophin-3, is paradoxically downregulated in cardiac hypertrophy

Haruko Kawaguchi-Manabe, Masaki Ieda, Kensuke Kimura, Tomohiro Manabe, Satoru Miyatake, Hideaki Kanazawa, Takashi Kawakami, Satoshi Ogawa, Makoto Suematsu, Keiichi Fukuda

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

The neurotrophin family plays pivotal roles in the development of the nervous system. Recently, the role of the neurotrophin in non-neural tissue has been extensively investigated. Among them, neurotrophin-3 and its receptor TrkC are critical for embryonic heart development, though little is known about neurotrophin-3/TrkC function in adult heart. Moreover, the expressions of other neurotrophin and Trk families in the cardiovascular system have not been fully determined. In adult and neonatal rats, only TrkC mRNA was expressed more abundantly in heart than aorta among the neurotrophin receptors, while all neurotrophins were equally expressed in the cardiovascular system. Immunohistochemistry confirmed the protein expressions of neurotrophin-3/TrkC in rat ventricles. In primary-cultured rat cardiomyocytes, neurotrophin-3 strongly activated p38 mitogen-activated protein kinase, extracellular signal-regulated kinase 1/2, and Jun N-terminal kinase pathways in Western blot analysis. In Northern blot analysis, neurotrophin-3 strongly increased mRNA expressions of cardiac hypertrophic markers (skeletal α-actin and atrial natriuretic peptide) in cardiomocytes. [3H]-phenylalanine uptake into cardiomyocytes, myofilament reorganization, and cardiomyocyte size were also augmented with neurotrophin-3 stimulation, indicating that neurotrophin-3 is a novel cardiac hypertrophic factor. Unexpectedly, neurotrophin-3 was downregulated in cardiac hypertrophy induced by pressure overload (in vivo), and in cardiomyocyte hypertrophy evoked by endothelin-1 stimulation (in vitro). Interestingly, the cell size and BNP mRNA expression level (markers of hypertrophy) were greater in cardiomyocytes treated with both neurotrophin-3 and endothelin-1 than in those stimulated with endothelin-1 alone. These findings demonstrate that neurotrophin-3 is a unique hypertrophic factor, which is paradoxically downregulated in cardiac hypertrophy and might counteract hypertrophic change.

Original languageEnglish
Pages (from-to)385-392
Number of pages8
JournalLife Sciences
Volume81
Issue number5
DOIs
Publication statusPublished - 2007 Jul 12

Keywords

  • Cardiac hypertrophy
  • Cardiomyocyte
  • Heart
  • Neurotrophin-3
  • TrkC

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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