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
Department of Regenerative Medicine and Advanced Cardiac Therapeutics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Circulation. 2006 Nov 28;114(22):2351-63. doi: 10.1161/CIRCULATIONAHA.106.627588. Epub 2006 Nov 13.
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.
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.
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.
调节心脏感觉神经系统的分子机制仍知之甚少。心脏感觉神经损伤会导致无症状性心肌缺血，这是糖尿病（DM）患者猝死的主要原因。本研究聚焦于神经生长因子（NGF）在调节心脏感觉神经系统中的作用，并分析DM患者无症状性心肌缺血的机制。
我们筛选了神经营养因子，发现心脏感觉神经的发育与心脏中合成的NGF平行。在NGF缺陷小鼠中，对降钙素基因相关肽、背根神经节（DRG）和背角呈免疫阳性的心脏伤害性感觉神经明显发育迟缓，而心脏特异性过表达NGF可挽救这些缺陷。在野生型和心脏中过表达NGF的转基因小鼠中，用链脲佐菌素诱导DM。在DM诱导的野生型小鼠中观察到NGF下调、降钙素基因相关肽免疫阳性的心脏感觉神经去神经支配以及DRG萎缩性改变，而在DM诱导的NGF转基因小鼠中这些恶化情况得到逆转。通过DRG中心肌缺血诱导的c-Fos表达来测量的心脏感觉功能，在野生型小鼠中也因DM而下调，但在NGF转基因小鼠中未下调。通过心肌缺血期间心脏传入神经的电生理活动确定，在糖尿病大鼠心脏中直接进行NGF基因转移可改善受损的心脏感觉神经支配和功能。
这些发现表明，心脏感觉神经系统的发育和调节依赖于心脏中合成的NGF，并且DM诱导的NGF减少会导致心脏感觉神经病变。
