title: Nerve growth factor is critical for cardiac sensory innervation and rescues neuropathy in diabetic hearts.
abstract: BACKGROUND
  Molecular mechanisms regulating the cardiac sensory nervous system remain poorly understood. Cardiac sensory nerve impairment causes silent myocardial ischemia, a main cause of sudden death in diabetes mellitus (DM). The present study focused on the roles of nerve growth factor (NGF) in the regulation of the cardiac sensory nervous system and analyzed the mechanism of silent myocardial ischemia in DM.
  
  
  RESULTS
  We screened neurotrophic factors and found that cardiac sensory nerves developed in parallel with NGF synthesized in the heart. Cardiac nociceptive sensory nerves that were immunopositive for calcitonin gene-related peptide, dorsal root ganglia (DRG), and the dorsal horn were markedly retarded in NGF-deficient mice, whereas cardiac-specific overexpression of NGF rescued these deficits. DM was induced with streptozotocin in wild-type and transgenic mice overexpressing NGF in the heart. Downregulation of NGF, calcitonin gene-related peptide-immunopositive cardiac sensory denervation, and atrophic changes in DRG were observed in DM-induced wild-type mice, whereas these deteriorations were reversed in DM-induced NGF transgenic mice. Cardiac sensory function, measured by myocardial ischemia-induced c-Fos expression in DRG, was also downregulated by DM in the wild-type mice but not in NGF transgenic mice. Direct gene transfer of NGF in the diabetic rat hearts improved impaired cardiac sensory innervation and function, determined by electrophysiological activity of cardiac afferent nerves during myocardial ischemia.
  
  
  CONCLUSIONS
  These findings demonstrate that the development and regulation of the cardiac sensory nervous system are dependent on NGF synthesized in the heart and that DM-induced NGF reduction causes cardiac sensory neuropathy.
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: Masaki
authors.initials: M
authors.lastname: Ieda
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kanazawa
authors.forename: Yasuyo
authors.initials: Y
authors.lastname: Ieda
authors.forename: Kensuke
authors.initials: K
authors.lastname: Kimura
authors.forename: Keisuke
authors.initials: K
authors.lastname: Matsumura
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Tomita
authors.forename: Takashi
authors.initials: T
authors.lastname: Yagi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Onizuka
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Shimoji
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ogawa
authors.forename: Shinji
authors.initials: S
authors.lastname: Makino
authors.forename: Motoaki
authors.initials: M
authors.lastname: Sano
authors.forename: Keiichi
authors.initials: K
authors.lastname: Fukuda
mesh_terms: D000344:Afferent Pathways / Q000502:physiology / Q000503:physiopathology; D000818:Animals; D003433:Crosses, Genetic; D003921:Diabetes Mellitus, Experimental / Q000235:genetics; D003929:Diabetic Neuropathies / Q000235:genetics*; D005260:Female; D018014:Gene Transfer Techniques; D006329:Heart Conduction System / Q000502:physiology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018995:Myosin Heavy Chains / Q000235:genetics; D020932:Nerve Growth Factor / Q000172:deficiency* / Q000235:genetics*; D011401:Promoter Regions, Genetic; D051381:Rats
chemical_list: D020932:Nerve Growth Factor; D018995:Myosin Heavy Chains