Loss of cardiac sympathetic neurotransmitters in heart  failure and NE infusion is associated with reduced NGF

Qin, Fuzhong; Vulapalli, Raju; Stevens, Suzanne Y.; Liang, Chang‐seng

doi:10.1152/ajpheart.00319.2001

Cited by 74 publications

(79 citation statements)

References 43 publications

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“…However, loss of any regulatory influences provided by norepinephrine (NE), the neurotransmitter released by sympathetic nerve terminals, also may contribute to the present findings. NE reduced NGF content in cardiac myocytes (Qin et al 2002), suggesting that a loss of NE supplied to peripheral targets may result in increased NGF protein.…”

Section: Ngf and Nt-3 Protein In Peripheral Tissues Following Denervamentioning

confidence: 97%

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Regulation of NGF and NT-3 protein expression in peripheral targets by sympathetic input

2007

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Nerve growth factor (NGF) and neurotrophin-3 (NT-3) are target-derived proteins that regulate innervating sympathetic neurons. Here, we used western blot analysis to investigate changes in NGF and NT-3 protein in several peripheral tissues following loss of sympathetic input. Following removal of the superior cervical ganglion (SCG), large molecular weight (MW) NGF species, including proNGF-A, were increased in distal intracranial SCG targets, such as pineal gland and extracerebral blood vessels (bv). Mature NGF was a minor species in these tissues and unchanged following sympathectomy. Large MW NGF species also were increased when sympathectomy was followed by in vivo NGF administration. Mature NT-3, which was abundant in controls, was significantly decreased in these targets following sympathetic denervation. The decrease in mature NT-3 was enhanced following NGF administration. The trigeminal ganglion, which provides sensory input to these targets, showed increased NGF, but decreased NT-3, in these treatments, demonstrating that decreased NT-3 at the targets did not result from enhanced NT-3 uptake. Unlike pineal gland and extracerebral bv, the external carotid artery, an extracranial proximal SCG target, showed no change in NGF following denervation, and mature NT-3 was significantly increased. Following NGF administration, NT-3 was significantly decreased. We provide evidence for sympathetic regulation of NGF and NT-3 in peripheral targets and that elevated NGF can depress NT-3. The differential response in distal and proximal adult targets is consistent with the idea that neurons innervating proximal and distal targets may serve different roles in regulating neurotrophin protein. In addition, we conclude that previous ELISA results showing increased NGF protein following sympathetic denervation may have resulted from increases in large MW species, rather than an increase in mature NGF.

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Section: Ngf and Nt-3 Protein In Peripheral Tissues Following Denervamentioning

confidence: 97%

“…These reports suggest a potential regulatory role by sympathetic input in the expression of target-derived neurotrophins in the peripheral nervous system. Indeed, norepinephrine (NE), the major neurotransmitter utilized by postganglionic sympathetic neurons, was shown to decrease NGF content in cardiac myocytes (Qin et al 2002).…”

Section: Introductionmentioning

confidence: 99%

Regulation of NGF and NT-3 protein expression in peripheral targets by sympathetic input

2007

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“…These differences may be related to the extent of infarction as larger infarcts can result in frank congestive heart failure, and this has been linked to cardiac NGF depletion and diminished sympathetic axon density (Kaye, et al, 2000;Qin, et al, 2002). Similarly, reduced NGF levels have been noted in patients with acute coronary symptoms as well as in atherosclerotic coronary vascular tissue (Chaldakov, et al, 2004;Manni, et al, 2005).…”

Section: Selectivity Of Post-infarct Hyperinnervationmentioning

confidence: 99%

Sympathetic hyperinnervation and inflammatory cell NGF synthesis following myocardial infarction in rats

et al. 2006

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Sympathetic hyperinnervation occurs in human ventricular tissue after myocardial infarction and may contribute to arrhythmias. Aberrant sympathetic sprouting is associated with elevated nerve growth factor (NGF) in many contexts, including ventricular hyperinnervation. However, it is unclear whether cardiomyocytes or other cell types are responsible for increased NGF synthesis. In this study, left coronary arteries were ligated and ventricular tissue examined in rats 1-28 days post-infarction. Infarct and peri-infarct tissue was essentially devoid of sensory and parasympathetic nerves at all time points. However, areas of increased sympathetic nerve density were observed in the peri-infarct zone between post-ligation days 4-14. Hyperinnervation occurred in regions containing accumulations of macrophages and myofibroblasts. To assess whether these inflammatory cells synthesize NGF, sections were processed for NGF in situ hybridization and immunohistochemistry. Both macrophage1 antigen-positive macrophages and α-smooth muscle actin immunoreactive myofibroblasts expressed NGF in areas where they were closely proximate to sympathetic nerves. To investigate whether NGF produced by peri-infarct cells induces sympathetic outgrowth, we cocultured adult sympathetic ganglia with peri-infarct explants. Neurite outgrowth from sympathetic ganglia was significantly greater at post-ligation days 7-14 as compared to control tissue. Addition of an NGF function-blocking antibody prevented the increased neurite outgrowth induced by periinfarct tissue. These findings provide evidence that inflammatory cell NGF synthesis plays a causal role in sympathetic hyperinnervation following myocardial infarction.

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“…13 In both experimental and clinical CHF, myocardial NGF expression is diminished. 14,15 To test the hypothesis of whether NGF improves the cardiac sympathetic nerve function in experimental CHF, NGF was directly injected into stellate ganglia of rats with transverse aortic constriction (TAC), which have been characterized previously by overt heart failure, depleted NE stores, and an impaired NE reuptake. 5,16 …”

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

et al. 2006

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Abstract-An impairment of cardiac norepinephrine reuptake through the neuronal norepinephrine transporter promotes depletion of cardiac norepinephrine stores and local cardiac sympathetic activation in heart failure. Nerve growth factor regulates differentiation and survival of adult sympathetic cells and is decreased in failing hearts. We hypothesized that injection of nerve growth factor into stellate ganglia normalizes cardiac norepinephrine homeostasis in experimental heart failure. Rats with transverse aortic constriction characterized by heart failure, depleted cardiac norepinephrine stores, and impaired cardiac norepinephrine reuptake were used as an experimental model. Nerve growth factor (20 g) or saline was directly injected into left stellate ganglia 4 weeks after transverse aortic constriction. Thirty-two hours after injection, determinants of cardiac norepinephrine homeostasis were measured. As compared with saline, nerve growth factor refilled depleted cardiac norepinephrine stores and improved cardiac [ 3 H]-norepinephrine uptake into isolated perfused hearts of transverse aortic constricted rats. In addition, pharmacological blockade of the norepinephrine transporter led to a higher increase in the overflow of endogenous norepinephrine from hearts of nerve growth factor-injected than saline-injected transverse aortic constricted rats. Norepinephrine transporter mRNA levels and the density of cardiac sympathetic nerves were not changed. Thirty-two hours after nerve growth factor injection, echocardiography revealed an increase in fractional shortening as compared with 2 days before injection. In conclusion, nerve growth factor attenuates local cardiac sympathetic overdrive of hypertrophic hearts by improving cardiac norepinephrine reuptake and might represent a novel therapeutic principle in the treatment of heart failure.

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Loss of cardiac sympathetic neurotransmitters in heart failure and NE infusion is associated with reduced NGF

Cited by 74 publications

References 43 publications

Regulation of NGF and NT-3 protein expression in peripheral targets by sympathetic input

Regulation of NGF and NT-3 protein expression in peripheral targets by sympathetic input

Sympathetic hyperinnervation and inflammatory cell NGF synthesis following myocardial infarction in rats

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

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