Reduced plasma levels of NGF and BDNF in patients with acute coronary syndromes

Manni, Luigi; Nikolova, Vesselka; Vyagova, D.; Chaldakov, George N.; Aloe, Luigi

doi:10.1016/j.ijcard.2004.10.041

Cited by 177 publications

(130 citation statements)

References 9 publications

Supporting

Mentioning

119

Contrasting

Unclassified

Order By: Relevance

“…Accordingly, it is possible that the association between low levels of BDNF and insulin resistance reflect underlying inflammatory processes. In addition, it has previously been described that patients with acute coronary syndromes have reduced levels of BDNF in plasma [38], which could further point to an association among inflammation, CVD and BDNF. In the present study, high CRP levels were found in participants with type 2 diabetes compared with those without type 2 diabetes, as reported elsewhere [39].…”

Section: Discussionmentioning

confidence: 93%

Brain-derived neurotrophic factor (BDNF) and type 2 diabetes

et al. 2006

View full text Add to dashboard Cite

Aims/hypothesis Decreased levels of brain-derived neurotrophic factor (BDNF) have been implicated in the pathogenesis of Alzheimer's disease and depression. These disorders are associated with type 2 diabetes, and animal models suggest that BDNF plays a role in insulin resistance. We therefore explored whether BDNF plays a role in human glucose metabolism. Subjects and methods We included (Study 1) 233 humans divided into four groups depending on presence or absence of type 2 diabetes and presence or absence of obesity; and (Study 2) seven healthy volunteers who underwent both a hyperglycaemic and a hyperinsulinaemic-euglycaemic clamp.Results Plasma levels of BDNF in Study 1 were decreased in humans with type 2 diabetes independently of obesity. Plasma BDNF was inversely associated with fasting plasma glucose, but not with insulin. No association was found between the BDNF G196A (Val66Met) polymorphism and diabetes or obesity. In Study 2 an output of BDNF from the human brain was detected at basal conditions. This output was inhibited when blood glucose levels were elevated. In contrast, when plasma insulin was increased while maintaining normal blood glucose, the cerebral output of BDNF was not inhibited, indicating that high levels of glucose, but not insulin, inhibit the output of BDNF from the human brain. Conclusions/interpretation Low levels of BDNF accompany impaired glucose metabolism. Decreased BDNF may be a pathogenetic factor involved not only in dementia and depression, but also in type 2 diabetes, potentially explaining the clustering of these conditions in epidemiological studies.

show abstract

Section: Discussionmentioning

confidence: 93%

Brain-derived neurotrophic factor (BDNF) and type 2 diabetes

et al. 2006

View full text Add to dashboard Cite

show abstract

“…In addition to our scientific findings, we have developed new tools to selectively detect mBDNF. Because recent studies have shown alterations in BDNF levels in the brains of Alzheimer's patients (28,29), in cerebrospinal fluid after brain injuries (30), and in various neurodegenerative disorders (31)(32)(33)(34), detecting the proBDNF/mBDNF ratio may serve as a biomarker in neuropsychiatric and neuropathological conditions.…”

Section: Activity-dependent Control Of Extracellular Probdnf 3 Mbdnf mentioning

confidence: 99%

Control of extracellular cleavage of ProBDNF by high frequency neuronal activity

Nagappan

Zaitsev

Senatorov

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

242

185

View full text Add to dashboard Cite

Pro-and mature neurotrophins often elicit opposing biological effects. For example, mature brain-derived neurotrophic factor (mBDNF) is critical for long-term potentiation induced by highfrequency stimulation, whereas proBDNF facilitate long-term depression induced by low-frequency stimulation. Because mBDNF is derived from proBDNF by endoproteolytic cleavage, mechanisms regulating the cleavage of proBDNF may control the direction of BDNF regulation. Using methods that selectively detect proBDNF or mBDNF, we show that low-frequency stimulation induced predominant proBDNF secretion in cultured hippocampal neurons. In contrast, high-frequency stimulation preferentially increased extracellular mBDNF. Inhibition of extracellular, but not intracellular cleavage of proBDNF greatly reduced high-frequency stimulationinduced extracellular mBDNF. Moreover, high-frequency, but not low-frequency stimulation selectively induced the secretion of tissue plasminogen activator, a key protease involved in extracellular proBDNF to mBDNF conversion. Thus, high-frequency neuronal activity controls the ratio of extracellular proBDNF/mBDNF by regulating the secretion of extracellular proteases. Our study demonstrates activity-dependent control of extracellular proteolytic cleavage of a secretory protein, and reveals an important mechanism that controls diametrically opposed functions of BDNF isoforms.BDNF ͉ hippocampus ͉ LTP ͉ proteases ͉ tPA B rain-derived neurotrophic factor (BDNF) plays a critical role in activity-dependent processes, such as synapse development and plasticity (1-3). Synthesized as a precursor, proBDNF is then sorted into one of the two secretory pathways: constitutive (passive) or regulated (induced or active) (4-6). Until recently, only mature BDNF (mBDNF) was considered biologically active. This view was challenged by findings that exogenous proBDNF induces apoptosis in peripheral neurons (7) and facilitates long-term depression (LTD) in the hippocampus (8). ProBDNF, is believed to be cleaved intracellularly by furin in trans-Golgi or by pro-protein convertase 1/3 (PC1/3) in secretory granules (9, 10) to generate mBDNF. Recently, Lee et al. demonstrated that proBDNF could be converted to mBDNF by extracellular proteases, such as plasmin and matrixmetalloprotease-7 (11). The physiological significance of extracellular proBDNF cleavage became evident when proBDNF 3 mBDNF conversion through the tissue plasminogen activator (tPA)/plasminogen cascade was shown to be essential for late phase long-term potentiation (L-LTP) in the hippocampus (12). Given the opposing biological effects of proBDNF and mBDNF, mechanisms controlling the cleavage of proBDNF have emerged as important mechanisms in controlling the direction of BDNF regulation (13).Neuronal release of endogenous proBDNF remains controversial. While studies using neuronal cultures in absence of glial cells and in the presence of cell impermeant ␣2 antiplasmin inhibitors successfully detected proBDNF in the extracellular culture medium (7), a recent study by Mat...

show abstract

“…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). Attenuation of NGF levels in cardiovascular dysfunctions therefore result in sympathetic denervation.…”

Section: Selectivity Of Post-infarct Hyperinnervationmentioning

confidence: 99%

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

et al. 2006

View full text Add to dashboard Cite

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.

show abstract

Reduced plasma levels of NGF and BDNF in patients with acute coronary syndromes

Cited by 177 publications

References 9 publications

Brain-derived neurotrophic factor (BDNF) and type 2 diabetes

Brain-derived neurotrophic factor (BDNF) and type 2 diabetes

Control of extracellular cleavage of ProBDNF by high frequency neuronal activity

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

Contact Info

Product

Resources

About