Nerve growth factor is critical for cardiac sensory innervation and rescues neuropathy in diabetic hearts

Masaki Ieda, Hideaki Kanazawa, Yasuyo Ieda, Kensuke Kimura, Keisuke Matsumura, Yuichi Tomita, Takashi Yagi, Takeshi Onizuka, Kenichiro Shimoji, Satoshi Ogawa, Shinji Makino, Motoaki Sano, Keiichi Fukuda

Research output: Contribution to journalArticle

71 Citations (Scopus)

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. METHODS AND 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.

Original languageEnglish
Pages (from-to)2351-2363
Number of pages13
JournalCirculation
Volume114
Issue number22
DOIs
Publication statusPublished - 2006 Nov

Fingerprint

Diabetic Neuropathies
Nerve Growth Factor
Diabetes Mellitus
Myocardial Ischemia
Spinal Ganglia
Nervous System
Transgenic Mice
Calcitonin Gene-Related Peptide
Down-Regulation
Nerve Growth Factors
Denervation
Streptozocin
Sudden Death
Cause of Death

Keywords

  • Diabetes mellitus
  • Gene therapy
  • Ischemia
  • Nervous system

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Nerve growth factor is critical for cardiac sensory innervation and rescues neuropathy in diabetic hearts. / Ieda, Masaki; Kanazawa, Hideaki; Ieda, Yasuyo; Kimura, Kensuke; Matsumura, Keisuke; Tomita, Yuichi; Yagi, Takashi; Onizuka, Takeshi; Shimoji, Kenichiro; Ogawa, Satoshi; Makino, Shinji; Sano, Motoaki; Fukuda, Keiichi.

In: Circulation, Vol. 114, No. 22, 11.2006, p. 2351-2363.

Research output: Contribution to journalArticle

Ieda, M, Kanazawa, H, Ieda, Y, Kimura, K, Matsumura, K, Tomita, Y, Yagi, T, Onizuka, T, Shimoji, K, Ogawa, S, Makino, S, Sano, M & Fukuda, K 2006, 'Nerve growth factor is critical for cardiac sensory innervation and rescues neuropathy in diabetic hearts', Circulation, vol. 114, no. 22, pp. 2351-2363. https://doi.org/10.1161/CIRCULATIONAHA.106.627588
Ieda, Masaki ; Kanazawa, Hideaki ; Ieda, Yasuyo ; Kimura, Kensuke ; Matsumura, Keisuke ; Tomita, Yuichi ; Yagi, Takashi ; Onizuka, Takeshi ; Shimoji, Kenichiro ; Ogawa, Satoshi ; Makino, Shinji ; Sano, Motoaki ; Fukuda, Keiichi. / Nerve growth factor is critical for cardiac sensory innervation and rescues neuropathy in diabetic hearts. In: Circulation. 2006 ; Vol. 114, No. 22. pp. 2351-2363.
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AU - Ieda, Masaki

AU - Kanazawa, Hideaki

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AU - Kimura, Kensuke

AU - Matsumura, Keisuke

AU - Tomita, Yuichi

AU - Yagi, Takashi

AU - Onizuka, Takeshi

AU - Shimoji, Kenichiro

AU - Ogawa, Satoshi

AU - Makino, Shinji

AU - Sano, Motoaki

AU - Fukuda, Keiichi

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N2 - 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. METHODS AND 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.

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KW - Diabetes mellitus

KW - Gene therapy

KW - Ischemia

KW - Nervous system

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