title: A novel cardiac hypertrophic factor, neurotrophin-3, is paradoxically downregulated in cardiac hypertrophy.
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 alpha-actin and atrial natriuretic peptide) in cardiomocytes. [(3)H]-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.
authors.affiliation: Department of Regenerative Medicine and Advanced Cardiac Therapeutics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Haruko
authors.initials: H
authors.lastname: Kawaguchi-Manabe
authors.forename: Masaki
authors.initials: M
authors.lastname: Ieda
authors.forename: Kensuke
authors.initials: K
authors.lastname: Kimura
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Manabe
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyatake
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kanazawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Kawakami
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ogawa
authors.forename: Makoto
authors.initials: M
authors.lastname: Suematsu
authors.forename: Keiichi
authors.initials: K
authors.lastname: Fukuda
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D006332:Cardiomegaly / Q000378:metabolism*; D015536:Down-Regulation; D004789:Enzyme Activation; D007150:Immunohistochemistry; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D020933:Neurotrophin 3 / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D020933:Neurotrophin 3; D020928:Mitogen-Activated Protein Kinases