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, Koki; Ogawa, Satoshi; Makino, Shinji; Sano, Motoaki; Fukuda, Keiichi

doi:10.1161/circulationaha.106.627588

Cited by 104 publications

(102 citation statements)

References 32 publications

(39 reference statements)

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“…In fact, Zahner et al report that vanilloid receptor-1-immunopositive sensory nerves are enriched in the epicardium but scarce in the myocardium (10). We show that cardiac sensory innervation is rich not only at epicardial sites but also in the ventricular myocardium and that sensory innervation increases with development (11). In a screen of several neurotrophic factors, we showed that development of cardiac sensory nerves coincides with synthesis of NGF in the heart.…”

Section: The Endothelin-1 (Et-1) / Ngf Pathway Is Critical For Cardiasupporting

confidence: 54%

New Aspects for the Treatment of Cardiac Diseases Based on the Diversity of Functional Controls on Cardiac Muscles: The Regulatory Mechanisms of Cardiac Innervation and Their Critical Roles in Cardiac Performance

Ieda

Fukuda

2009

J Pharmacol Sci

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Abstract. The heart is abundantly innervated, and the nervous system precisely controls the function of this organ. The density of cardiac innervation is altered in diseased hearts, which can lead to unbalanced neural activation and lethal arrhythmia. For example, diabetic sensory neuropathy causes silent myocardial ischemia, characterized by loss of pain perception during myocardial ischemia, and it is a major cause of sudden cardiac death in diabetes mellitus. Despite the clinical importance of cardiac innervation, the mechanisms underlying the control of this process remain poorly understood. We demonstrate that cardiac innervation is determined by the balance between neural chemoattractants and chemorepellents within the heart. Nerve growth factor (NGF), a potent chemoattractant, is synthesized abundantly by cardiomyocytes, and is induced by the upregulation of endothelin-1 during development. By comparison, the neural chemorepellent Sema3a is expressed at high levels in the subendocardium in the early stage of embryogenesis and is downregulated as development progresses, leading to epicardial-toendocardial transmural sympathetic innervation patterning. We also show that the downregulation of cardiac NGF is a cause of diabetic neuropathy and that NGF supplementation prevents silent myocardial ischemia in diabetes mellitus. Both Sema3a-targeted and Sema3a-overexpressing mice display sudden cardiac death or lethal arrhythmias due to disruption of innervation patterning. The present review focuses on the regulatory mechanisms controlling cardiac innervation and the critical roles of these processes in cardiac performance.

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Section: The Endothelin-1 (Et-1) / Ngf Pathway Is Critical For Cardiasupporting

confidence: 54%

New Aspects for the Treatment of Cardiac Diseases Based on the Diversity of Functional Controls on Cardiac Muscles: The Regulatory Mechanisms of Cardiac Innervation and Their Critical Roles in Cardiac Performance

Ieda

Fukuda

2009

J Pharmacol Sci

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“…Based on the present study, we formulate a possible theory for the susceptibility of the diabetic hearts to ischemic injury, which is that the damage of sensory nerve fibers induced by diabetes causes the decline in the expression and function of TRPV1, and the latter results in the deterioration of cardiac sensory function and consequently the failure of the perception of noxious signals, eventually rendering the diabetic hearts vulnerable to the ischemic injury. 30 As is mentioned above, TRPV1 is closely related with CGRP as CGRP coexists in the TRPV1-positive sensory nerves in the hearts of rats, pigs, and human. 31 The activation of TRPV1 results in the release of CGRP, which in turn exerts cardioprotective effects.…”

Section: Discussionmentioning

confidence: 91%

Decreased Expression of Transient Receptor Potential Vanilloid 1 Impaires the Postischemic Recovery of Diabetic Mouse Hearts

Wei

Wang

Han

et al. 2009

Circ J

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iabetes mellitus (DM) is one of the most important risk factors of cardiovascular diseases, and numerous patients who are afflicted with diabetes usually suffer the diffused stenosis of coronary arteries, leading to dreadful consequences such as myocardial infarction and cardiomyopathy. Non-invasive evaluation tools such as Doppler echocardiography demonstrate the impairment of cardiac function in diabetic animal models as well as in diabetic patients, 1,2 whereas the mechanism is still not well elucidated.Neuropathy is one of the common complications of diabetes, which could result in the degeneration of the nerve fibers both in diabetic animals and patients. 3-5 Transient Receptor Potential Vanilloid 1 (TRPV1) is a non-selective cation channel and is diversely distributed in terminals of sensory nerve fibers, dorsal root ganglia (DRG), spinal cord, and many other various regions in the brain. 6 It could lead to the release of neurotransmitters such as calcitonin generelated peptide (CGRP) from peripheral nerve terminals when activated by capsaicin, protons, noxious heat, etc. 7,8 It has been found that in diabetes-prone NOD mice, the protein expression and function of TRPV1 was significantly depressed in DRG. 9 Using immunohistochemical staining, TRPV1 was also found to be reduced in epineurial arterioles in long-term diabetic rats. 10 These investigations suggest that the expression of TRPV1 is susceptible to diabetes. In addition, recent studies disclose that TRPV1 is expressed in the myocardium and perivascular region, which are close to the epicardial surface of ventricles. 11 We revealed that the expression of TRPV1 in diabetic hearts was significantly suppressed in our previous study. 12 However, the impact of the decreased TRPV1 on the diabetic heart has not been investigated yet.A few studies have revealed that TRPV1 can serve as a molecular integrator of various noxious stimuli, especially the myocardial ischemia, in order to protect the hearts against ischemic injury. 11,13 For example, exogenous agonists of TRPV1 exert a cardioprotective effect on ischemia/reperfusion injury, whereas TRPV1 gene knockout eliminates the protection. 14,15 Therefore, it is reasonable to hypothesize that the alteration of TRPV1 secondary to diabetes can be related to the severe postischemic injury of the heart.In the present study, we measure the expression of TRPV1 and CGRP in diabetic hearts and investigate the effect of TRPV1 on the cardiac function after ischemia injury. The results might help explain the vulnerability of diabetic hearts to ischemic injury.

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“…Upregulation of both NGF and GDNF was demonstrated in rats with Trypanozoma cruzi infection (Chagas disease) causing sympathetic as well as parasympathetic denervation (15). GDNF was also demonstrated to express in the hearts of murine embryos and neonates by quantitative RT-PCR (11). In addition, artemin, a neurotrophic factor of the GDNF family was shown to express along blood vessels in the early developmental stages and promote the development of sympathetic innervation of blood vessels (3,8).…”

mentioning

confidence: 99%

Glial cell line-derived neurotrophic factor (GDNF) enhances sympathetic neurite growth in rat hearts at early developmental stages

Miwa¹,

Lee²,

Takagishi³

et al. 2010

Biomed. Res.

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Molecular signaling of sympathetic innervation of myocardium is an unresolved issue. The purpose of this study was to investigate the effect of neurotrophic factors on sympathetic neurite growth towards cardiomyocytes. Cardiomyocytes (CMs) and sympathetic neurons (SNs) were isolated from neonatal rat hearts and superior cervical ganglia, and were co-cultured, either in a random or localized way. Neurite growth from SNs toward CMs was assessed by immunohistochemistry for neurofilament M and α-actinin in response to neurotrophic factors-nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), ciliary neurotrophic factor (CNTF) and a chemical repellent, semaphorin 3A. As a result, GDNF as well as NGF and BDNF stimulated neurite growth. GDNF enhanced neurite outgrowth even under the NGF-depleted culture condition, excluding an indirect effect of GDNF via NGF. Quantification of mRNA and protein by real-time PCR and immunohistochemistry at different developmental stages revealed that GDNF is abundantly expressed in the hearts of embryos and neonates, but not in adult hearts. GDNF plays an important role in inducing cardiac sympathetic innervation at the early developmental stages. A possible role in (re)innervation of injured or transplanted or cultured and transplanted myocardium may deserve investigation.

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

Cited by 104 publications

References 32 publications

New Aspects for the Treatment of Cardiac Diseases Based on the Diversity of Functional Controls on Cardiac Muscles: The Regulatory Mechanisms of Cardiac Innervation and Their Critical Roles in Cardiac Performance

New Aspects for the Treatment of Cardiac Diseases Based on the Diversity of Functional Controls on Cardiac Muscles: The Regulatory Mechanisms of Cardiac Innervation and Their Critical Roles in Cardiac Performance

Decreased Expression of Transient Receptor Potential Vanilloid 1 Impaires the Postischemic Recovery of Diabetic Mouse Hearts

Glial cell line-derived neurotrophic factor (GDNF) enhances sympathetic neurite growth in rat hearts at early developmental stages

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