Regulation of nerve growth factor in the heart: The role of the calcineurin–NFAT pathway

Rana, Obaida R.; Saygili, Erol; Meyer, Christian; Gemein, Christopher; Krüttgen, Alex; Andrzejewski, Michael G.; Ludwig, Andreas; Schotten, Ulrich; Schwinger, Robert H. G.; Weber, Christian; Weis, Joachim; Mischke, Karl; Rassaf, Tienush; Kelm, Malte; Schauerte, Patrick

doi:10.1016/j.yjmcc.2008.12.006

Cited by 42 publications

(36 citation statements)

References 34 publications

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“…These findings together indicated that ET-1 is a key regulator of NGF expression in cardiomyocytes, and that the ET-1/NGF pathway is critical for sympathetic innervation in the heart. 37 In contrast to this NGF upregulation by ET-1, mechanical stretch and ␣-1-adrenergic stimulation downregulated NGF via activation of the calcineurin-NFAT pathway and subsequent stimulation of myocytes, resulting in decreased neurite outgrowth 42 Meanwhile, inhibition of the myocyte calcineurin-nuclear factor of activated T-cells (NFAT) pathway increased neurite outgrowth of cardiac sympathetic neurons in vitro. Further in vivo studies are needed to confirm the role of calcineurin-NFAT/NGF signaling in the developing cardiac sympathetic nervous system.…”

Section: Neurotrophic Factors Are Critical Chemoattractants For Cardimentioning

confidence: 99%

“…42,119,120 Furthermore, Saygili et al 121 recently demonstrated different signaling routes of NGF expression activated under conditions of high-frequency electric field stimulation, mimicking atrial fibrillation (AF), in neonatal rat ventricular myocytes. These authors showed that the ET-1 cascade could upregulate NGF expression during irregular stimulation (eg, atrial fibrillation with moderate ventricular response), whereas the calcineurin-NFAT pathway was activated in rapid stimulation, resulting in NGF downregulation and cardiac hypertrophy (eg, tachycardia-induced cardiomyopathy).…”

Section: Sympathetic Dysfunction In Heart Failurementioning

confidence: 99%

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Development, Maturation, and Transdifferentiation of Cardiac Sympathetic Nerves

Kimura

Ieda

Fukuda

2012

Circulation Research

142

120

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Abstract:The heart is electrically and mechanically controlled as a syncytium by the autonomic nervous system. The cardiac nervous system comprises the sympathetic, parasympathetic, and sensory nervous systems that together regulate heart function on demand. Sympathetic electric activation was initially considered the main regulator of cardiac function; however, modern molecular biotechnological approaches have provided a new dimension to our understanding of the mechanisms controlling the cardiac nervous system. The heart is extensively innervated, although the innervation density is not uniform within the heart, being high in the subepicardium and the special conduction system. We and others showed previously that the balance between neural chemoattractants and chemorepellents determine cardiac nervous development, with both factors expressed in heart. Nerve growth factor is a potent chemoattractant synthesized by cardiomyocytes, whereas Sema3a is a neural chemorepellent expressed specifically in the subendocardium. Disruption of this wellorganized molecular balance and innervation density can induce sudden cardiac death due to lethal arrhythmias. In diseased hearts, various causes and mechanisms underlie cardiac sympathetic abnormalities, although their detailed pathology and significance remain contentious. We reported that cardiac sympathetic rejuvenation occurs in cardiac hypertrophy and, moreover, interleukin-6 cytokines secreted from the failing myocardium induce cholinergic transdifferentiation of the cardiac sympathetic system via a gp130 signaling pathway, affecting cardiac performance and prognosis. In this review, we summarize the molecular mechanisms involved in sympathetic development, maturation, and transdifferentiation, and propose their investigation as new therapeutic targets for heart disease. (Circ Res. 2012;110:325-336.) Key Words: cardiac sympathetic nervous system Ⅲ cardiac innervation patterning Ⅲ nerve growth factor Ⅲ cardiac rejuvenation Ⅲ cholinergic transdifferentiation Ⅲ IL-6 cytokines H eart tissue is extensively innervated via the autonomic nervous system, which comprises sympathetic and parasympathetic nerves. The cardiac sympathetic nervous system (SNS) uses norepinephrine (NE) as a neurotransmitter and increases the heart rate (chronotropic) and conduction velocity (dromotropic), as well as myocardial contraction (inotropic) and relaxation (lusitrophic). Sympathetic innervation density, which is highest in the subepicardium and central conduction system, is stringently regulated in the heart. 1 Regional differences in sympathetic innervation correspond to different areas of influence over cardiac function that cooperate to effectively control cardiac performance. Despite the clinical importance of cardiac innervation, little is known about the developmental and regulatory mechanisms underlying sympathetic innervation patterning.Cardiac innervation density is altered in pathological hearts, such as after myocardial infarction (MI), 2 in which the cardiac nerves undergo Walleria...

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Section: Neurotrophic Factors Are Critical Chemoattractants For Cardimentioning

confidence: 99%

Section: Sympathetic Dysfunction In Heart Failurementioning

confidence: 99%

Development, Maturation, and Transdifferentiation of Cardiac Sympathetic Nerves

Kimura

Ieda

Fukuda

2012

Circulation Research

142

120

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“…13 PCR primers and fluorogenic probes for NGF, BDNF, CNTF, GDNF, NT-3, and the endogenous control were purchased from Applied Biosystems (Foster City, CA). The assay numbers were as follows: Rn01533872_m1 (Ngfb), Rn00560868_m1 (Bdnf), Rn00755092_m1 (Cntf), Rn00569510_m1 (Gdnf), Rn00579280_m1 (Ntf3), Rn00560865_m1 (␤-2 microglobulin).…”

Section: High-frequency Electric Field Stimulation Of Nigpmentioning

confidence: 99%

Chronic Electrical Neuronal Stimulation Increases Cardiac Parasympathetic Tone by Eliciting Neurotrophic Effects

Rana

Saygili

Gemein

et al. 2011

Circulation Research

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Rationale: Recently, we provided a technique of chronic high-frequency electric stimulation (HFES) of the right inferior ganglionated plexus for ventricular rate control during atrial fibrillation in dogs and humans. In these experiments, we observed a decrease of the intrinsic ventricular rate during the first 4 to 5 months when HFES was intermittently shut off.Objective: We thus hypothesized that HFES might elicit trophic effects on cardiac neurons, which in turn increase baseline parasympathetic tone of the atrioventricular node. Methods and Results:In mongrel dogs atrial fibrillation was induced by rapid atrial pacing. Endocardial HFES of the right inferior ganglionated plexus, which contains abundant fibers to the atrioventricular node, was performed for 2 years. Sham-operated nonstimulated dogs served as control. In chronic neurostimulated dogs, we found an increased neuronal cell size accompanied by an increase of choline acetyltransferase and unchanged tyrosine hydroxylase protein expression as compared with unstimulated dogs. Moreover, ␤-nerve growth factor (NGF) and neurotrophin (NT)-3 were upregulated in chronically neurostimulated dogs. In vitro, HFES of cultured neurons of interatrial ganglionated plexus from adult rats increased neuronal growth accompanied by upregulation of NGF, NT-3, glial-derived neurotrophic factor (GDNF), ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF) expression. NGF was identified as the main growth-inducing factor, whereas NT-3 did not affect HFES-induced growth. However, NT-3 could be identified as an important acetylcholine-upregulating factor. Key Words: atrial fibrillation Ⅲ tachyarrhythmias Ⅲ acetylcholine Ⅲ nervous system D uring the last 10 years, techniques have been developed to directly and selectively interfere with the intrinsic cardiac neural system via electric stimulation catheters or leads in animals and patients. [1][2][3][4][5] The baseline observation for these applications was that depolarization of intracardiac neural fibers by high-frequency electric stimulation (HFES) delivers neurotransmitters that subsequently act locally on cardiac structures (eg, stimulation of sympathetic fibers along the coronary sinus selectively increases left ventricle inotropy). 5 Furthermore, acute, short-term endocardial HFES of the right inferior ganglionated plexus (RIGP) elicits selective negative dromotropic effects in awake patients and slows atrioventricular (AV) conduction during atrial fibrillation. 3 The RIGP is located between the inferior caval vein, the left atrium and the ostium of the coronary sinus. It contains abundant parasympathetic fibers that affect AV node conduction. 6,7 After proof of concept in humans, we and others developed a technique for chronic endocardial 8,9 and epicardial 10 neurostimulation of the RIGP for ventricular rate control during atrial fibrillation (AF) in dogs. Of note, the negative dromotropic effect during endocardial HFES could be maintained throughout the entire neurostimulation period of 2 year...

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“…The interaction between NGF and its receptor in cardiomyocytes causes a prosurvival signal of transcriptional factors [31]. For several cardiac diseases (MI, CAD) Rana and colleagues reported that cellular stretch leads to a decrease of NGF mRNA and protein expression in cardiomyocytes [32]. Therefore CABG, which aims to create a new pathway for blood flow that ensures the delivery of oxygen and nutrients to the heart muscle, could improve these conditions in patients with CAD.…”

Section: Discussionmentioning

confidence: 99%

Reduced NGF-Serum Concentrations in Coronary Artery Disease Patients Increase after Coronary Artery Bypass Grafting

Köhler¹

2012

J Clin Exp Cardiolog

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Background: Coronary Artery Disease (CAD) is the leading cause of death worldwide, but neurological deficits are the most devastating complications of its treatment, Coronary Artery Bypass Surgery (CABG). As Nerve Growth Factor (NGF) has been implicated in the modulation of inflammatory and fibroproliferative mechanisms leading to atherosclerosis as well as in neuroprotection and survival of neurons, the time course of NGF serum concentrations during CABG has been studied. Methods:Twenty-six male patients were scheduled for coronary artery bypass grafting and NGF levels have been measured 1 hour before the operation started and 2, 5 and 120 hours postoperatively. Pre-operation values of NGFs were compared to healthy controls. Results:We found significantly lower NGF serum concentrations in coronary artery disease patients (n=26, age: 68.8 ± 5.5 years, mean NGF: 13.04 ± 32.1 pg/ml) as compared to age-matched healthy controls (n=20, age: 64.35 ± 4.15, mean NGF: 29.54 ± 24.23 pg/ml). A significant increase of NGF was found 120 hours after operation (Z=3.26, p=0.001).Conclusion: NGF seems to be decreased in coronary artery disease and is increased by operative coronary revascularization procedures. Changes occurring during cardiac surgery may indicate beneficial regenerative processes but may also implicate neuronal alterations induced by operative procedures.

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Regulation of nerve growth factor in the heart: The role of the calcineurin–NFAT pathway

Cited by 42 publications

References 34 publications

Development, Maturation, and Transdifferentiation of Cardiac Sympathetic Nerves

Development, Maturation, and Transdifferentiation of Cardiac Sympathetic Nerves

Chronic Electrical Neuronal Stimulation Increases Cardiac Parasympathetic Tone by Eliciting Neurotrophic Effects

Reduced NGF-Serum Concentrations in Coronary Artery Disease Patients Increase after Coronary Artery Bypass Grafting

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