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(Circulation. 2006;114:2351-2363.)
© 2006 American Heart Association, Inc.

Molecular Cardiology

Nerve Growth Factor Is Critical for Cardiac Sensory Innervation and Rescues Neuropathy in Diabetic Hearts

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

From the Department of Regenerative Medicine and Advanced Cardiac Therapeutics (M.I., H.K., Y.I., K.K., K.M., Y.T., T.Y., T.O., K.S., S.M., M.S., K.F.) and Cardiopulmonary Division, Department of Internal Medicine (M.I., H.K., K.M., T.Y., T.O., K.S., S.O.), Keio University School of Medicine, Tokyo, Japan.

Reprint requests to Keiichi Fukuda, MD, PhD, Department of Regenerative Medicine and Advanced Cardiac Therapeutics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. E-mail kfukuda{at}sc.itc.keio.ac.jp

Received March 19, 2006; revision received August 14, 2006; accepted September 8, 2006.

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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