title: Cardiac sympathetic rejuvenation: a link between nerve function and cardiac hypertrophy.
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 beta(3)-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 [(125)I]-metaiodobenzylguanidine and [(3)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.
authors.affiliation: Department of Regenerative Medicine and Advanced Cardiac Therapeutics, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Kimura
authors.forename: Masaki
authors.initials: M
authors.lastname: Ieda
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kanazawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Yagi
authors.forename: Makoto
authors.initials: M
authors.lastname: Tsunoda
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Ninomiya
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kurosawa
authors.forename: Kenji
authors.initials: K
authors.lastname: Yoshimi
authors.forename: Hideki
authors.initials: H
authors.lastname: Mochizuki
authors.forename: Kazuto
authors.initials: K
authors.lastname: Yamazaki
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ogawa
authors.forename: Keiichi
authors.initials: K
authors.lastname: Fukuda
mesh_terms: D000320:Adrenergic Fibers / Q000502:physiology*; D000818:Animals; D004298:Dopamine / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism; D019922:GAP-43 Protein / Q000378:metabolism; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000503:physiopathology; D006352:Heart Ventricles / Q000294:innervation* / Q000503:physiopathology*; D006976:Hypertension, Pulmonary / Q000150:complications*; D017380:Hypertrophy, Right Ventricular / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D007700:Kinetics; D008297:Male; D016686:Monocrotaline; D032383:Myocytes, Cardiac / Q000378:metabolism; D020932:Nerve Growth Factor / Q000235:genetics / Q000502:physiology; D039842:Neural Cell Adhesion Molecule L1 / Q000378:metabolism; D009638:Norepinephrine / Q000096:biosynthesis / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012794:Sialic Acids / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D019332:Endothelin-1; D019922:GAP-43 Protein; D039842:Neural Cell Adhesion Molecule L1; D012794:Sialic Acids; C488416:Tubb3 protein, rat; D014404:Tubulin; C103469:polysialyl neural cell adhesion molecule; D016686:Monocrotaline; D020932:Nerve Growth Factor; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine; D009638:Norepinephrine