Endothelin-1 regulates cardiac sympathetic innervation in the rodent heart by controlling nerve growth factor expression

Abstract

IntroductionCardiac tissues are extensively innervated by autonomic nerves. The cardiac sympathetic nerve plays an important role in modulating heart rate, conduction velocity, myocardial contraction, and relaxation. Although several molecules that regulate the development of the heart have been well characterized, little is known about the mechanism that regulates sympathetic innervation of the heart. The cardiac sympathetic nerve extends from the sympathetic neuron in stellate ganglia (SG), which is derived from the neural crest (1). Nerve growth factor (NGF) is a prototypic member of the neurotrophin family, members of which are critical for the differentiation, survival, and synaptic activity of the peripheral sympathetic and sensory nervous systems (2, 3). Levels of NGF expression within innervated tissues roughly correspond to innervation density (4). The volume of sympathetic ganglion is reduced by at least 80% at postnatal day 3 in mice with a disruption of the NGF gene. In mice that lack the NGF receptor TrkA, no neurons remain at postnatal day 9 (2). Deletion of a single copy of the NGF gene results in a 50% reduction in sympathetic neurons (5), while overexpression of NGF in the heart results in cardiac hyperinnervation and hyperplasia in SG neurons (6). These results demonstrate the importance of NGF in the regulation of sympathetic neuron development and innervation.In pathological states, NGF production in the heart is variable. In ischemic hearts, an increase in cardiac NGF leads to regeneration of sympathetic nerves (7,8). In a previous experiment, we found that NGF was upregulated in streptozotocin-induced diabetic murine hearts (9). In contrast, it was reported that NGF and sympathetic innervation were reduced in congestive heart failure (10). Despite their importance, the molecular mechanisms that regulate NGF expression and sympathetic innervation in the heart remain poorly understood.Endothelin-1 (ET-1) is believed to play a critical role in the pathogenesis of cardiac hypertrophy, hypertension, and atherosclerosis. Gene targeting of ET-1 and its receptor endothelin-A (ET A ) resulted in unexpected craniofacial and cardiovascular abnormalities. These phenotypes are consistent with interference of neural crest differentiation. The influence of ET-1 on neural crest development remains undetermined (11-13).We hypothesized that ET-1 could affect the induction of neurotrophic factors, and that its disruption might contribute to the immature development of neural crest-derived cells. In this study, we found ET-1-specific induction of NGF in cardiomyocytes, idenEndothelin-1 regulates cardiac sympathetic innervation in the rodent heart by controlling nerve growth factor expression The cardiac sympathetic nerve plays an important role in regulating cardiac function, and nerve growth factor (NGF) contributes to its development and maintenance. However, little is known about the molecular mechanisms that regulate NGF expression and sympathetic innervation of the heart. In an effort to identify regulato...

Age-related regional differences in cardiac nerve growth factor expression

“…Endothelin-1 (ET-1) has been shown to regulate the expression of NGF in the rodent heart (Ieda et al 2004), and its endogenous expression is required for cardiomyocyte survival (Zhao et al 2006). In the present study, we found that the expression of ET-1 in LA and RA positively correlated with the expression of NGF, with respect to age.…”

“…Thus, the observed decrease of TrkA in the ventricles in O rats fits well to the parallel increase of NGF. Likewise, a downregulation of ET-1 expression may reflect a negative feedback loop of increased NGF levels since ET-1 has been shown to regulate the expression of NGF in the rodent heart (Ieda et al 2004). The concordant course of NGF and TrkA in the atria, by contrast, may point to a differential and probably multifactorial regulation of TrkA expression in the atria by yet unknown additional contributors.…”

Biallelic SEMA3A defects cause a novel type of syndromic short stature

“…Sema3a has been identified as the chemorepellent agent inducing growth cone collapse and repelling sympathetic axons in the heart, as opponent of NGF, reported to be required for active sympathetic axon growth and innervation in the heart [Ieda et al, 2004[Ieda et al, , 2007Kuruvilla et al, 2004]. It could be shown that mice targeted with Sema3a or those overexpressing the gene display sudden cardiac death or lethal arrhythmias due to disruption of innervation patterning.…”

“…Apart from its role within the central neuronal system, SEMA3A is also important for development and plasticity of the peripheral system contributing to cardiac sympathetic innervation, and T-cell migration [Ieda et al, 2004[Ieda et al, , 2007Garcia et al, 2011]. SEMA3A is also distinctively and differentially expressed in spinal cord motor neurons and its signaling controls the timing of motor axon ingrowth to the limb [Cohen et al, 2005;Huber et al, 2005].…”

Injection of Nerve Growth Factor Into Stellate Ganglia Improves Norepinephrine Reuptake Into Failing Hearts

“…16 Additional studies are warranted to test the possibility of whether NGF interferes with the ET-1 signaling cascade. Ieda et al 31 reported, vice versa, that ET-1 regulates cardiac sympathetic innervation by controlling NGF expression through an endothelin A receptor-and PKC-dependent pathway. In this regard, the NGF-mediated improvement of cardiac sympathetic function in TAC rats might represent a negative feedback loop because of an activated ET-1 system.…”