Nerve growth factor is critical for cardiac sensory innervation and rescues neuropathy in diabetic hearts
Nerve growth factor is critical for cardiac sensory innervation and rescues neuropathy in diabetic hearts
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DOI：
10.1161/circulationaha.106.627588
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发表时间：
2006-11-28
期刊：
影响因子：
37.8
通讯作者：
Fukuda, Keiichi
中科院分区：
文献类型：
--
作者：
Ieda, Masaki;Kanazawa, Hideaki;Fukuda, Keiichi
背景-调节心脏感觉神经系统的分子机制仍然知之甚少.心脏感觉神经损伤引起无症状心肌缺血，是糖尿病（DM）猝死的主要原因。本研究的重点是神经生长因子（NGF）在心脏感觉神经系统的调节作用，并分析了DM的无症状心肌缺血的机制。方法和结果-我们筛选神经营养因子，发现心脏感觉神经与心脏合成的NGF平行发展。降钙素基因相关肽、背根神经节（DRG）和背角免疫阳性的心脏伤害性感觉神经在NGF缺陷小鼠中明显延迟，而心脏特异性NGF过表达挽救了这些缺陷。糖尿病诱导与链脲佐菌素在野生型和转基因小鼠过度表达神经生长因子在心脏。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心脏感觉去神经支配和DRG萎缩性变化，而这些恶化在DM诱导的NGF转基因小鼠中被逆转。心脏感觉功能，心肌缺血诱导的c-Fos在DRG中的表达，也下调DM在野生型小鼠，但不是在NGF转基因小鼠。直接基因转移的神经生长因子在糖尿病大鼠的心脏改善受损的心脏感觉神经支配和功能，由心肌缺血期间的心脏传入神经的电生理活动确定。结论-这些研究结果表明，心脏感觉神经系统的发展和调节依赖于神经生长因子在心脏中合成，DM诱导的神经生长因子减少导致心脏感觉神经病变。
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.