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Role of Hypoxia-Induced Brain Derived Neurotrophic Factor in Human Pulmonary Artery Smooth Muscle.

Hartman W, Helan M, Smelter D, Sathish V, Thompson M, Pabelick CM, Johnson B, Prakash YS - PLoS ONE (2015)

Bottom Line: Recent studies suggest that growth factors called neurotrophins, particularly brain-derived neurotrophic factor (BDNF), can influence lung structure and function, and their role in the pulmonary artery warrants further investigation.In arteries of patients with pulmonary hypertension, BDNF expression and release was higher at baseline.Accordingly, the BDNF-TrkB system could be a key player in the pathogenesis of hypoxia-induced pulmonary vascular diseases, and thus a potential target for therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota, 55905, United States of America.

ABSTRACT

Background: Hypoxia effects on pulmonary artery structure and function are key to diseases such as pulmonary hypertension. Recent studies suggest that growth factors called neurotrophins, particularly brain-derived neurotrophic factor (BDNF), can influence lung structure and function, and their role in the pulmonary artery warrants further investigation. In this study, we examined the effect of hypoxia on BDNF in humans, and the influence of hypoxia-enhanced BDNF expression and signaling in human pulmonary artery smooth muscle cells (PASMCs).

Methods and results: 48h of 1% hypoxia enhanced BDNF and TrkB expression, as well as release of BDNF. In arteries of patients with pulmonary hypertension, BDNF expression and release was higher at baseline. In isolated PASMCs, hypoxia-induced BDNF increased intracellular Ca2+ responses to serotonin: an effect altered by HIF1α inhibition or by neutralization of extracellular BDNF via chimeric TrkB-Fc. Enhanced BDNF/TrkB signaling increased PASMC survival and proliferation, and decreased apoptosis following hypoxia.

Conclusions: Enhanced expression and signaling of the BDNF-TrkB system in PASMCs is a potential mechanism by which hypoxia can promote changes in pulmonary artery structure and function. Accordingly, the BDNF-TrkB system could be a key player in the pathogenesis of hypoxia-induced pulmonary vascular diseases, and thus a potential target for therapy.

No MeSH data available.


Related in: MedlinePlus

BDNF/TrkB in hypoxia effects on PASMC survival.Western blots for pPI3k, pAkt, and pERK in denuded human PA (aand b). After 24 hr hypoxia exposure, PI3 kinase (c) and pAkt/Akt (d) levels were both increased: effects blunted by BDNF neutralization or HIF1α inhibition. In normoxia, 100 pM BDNF enhanced PI3 kinase expression and Akt phosphorylation. 24h hypoxia also enhanced phosphorylation of ERK1/2 (e). In normoxia, 100 pM BDNF enhanced ERK1/2 phosphorylation. Extracellular neutralization of BDNF using TrkB-Fc (1 μg/ml) or inhibition of HIF1α blunted hypoxia effects on ERK phosphorylation. Values are means ± SE (n = 3 patients). *Significant difference from normoxia control; # significant inhibitor effect from hypoxia control (p<0.05).
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pone.0129489.g005: BDNF/TrkB in hypoxia effects on PASMC survival.Western blots for pPI3k, pAkt, and pERK in denuded human PA (aand b). After 24 hr hypoxia exposure, PI3 kinase (c) and pAkt/Akt (d) levels were both increased: effects blunted by BDNF neutralization or HIF1α inhibition. In normoxia, 100 pM BDNF enhanced PI3 kinase expression and Akt phosphorylation. 24h hypoxia also enhanced phosphorylation of ERK1/2 (e). In normoxia, 100 pM BDNF enhanced ERK1/2 phosphorylation. Extracellular neutralization of BDNF using TrkB-Fc (1 μg/ml) or inhibition of HIF1α blunted hypoxia effects on ERK phosphorylation. Values are means ± SE (n = 3 patients). *Significant difference from normoxia control; # significant inhibitor effect from hypoxia control (p<0.05).

Mentions: Hypoxia has been previously shown to enhance PASMC survival and proliferation,[10,11,41] acting through pathways such as pPI3K and pAkt/Akt [25,42,43] which happen to overlap with BDNF signaling.[25] Representative Western blots are shown in Fig 5A and 5B. Following BDNF exposure in either normoxia or hypoxia, enhanced pPI3K and pERK until approximately 30 minutes of BDNF treatment were noted. No short term enhancement of pAkt was observed with BDNF. At 24h, however, (Fig 5B) enhanced phospho-protein expression was observed in the presence of BDNF, particularly pPI3K (Fig 5B) and pAkt (Fig 5C). Hypoxia alone also upregulated expression of these proteins. While the additional presence of BDNF did not further enhance pPI3K or pAkt/Akt levels in hypoxia, both the HIF1α inhibitor, and TrkB-Fc reduced expression of these pro-survival proteins in hypoxia exposed tissues (Fig 5B and 5C; n = 3 for each group; p<0.05 for BDNF, HIF1α inhibitor and TrkB-Fc).


Role of Hypoxia-Induced Brain Derived Neurotrophic Factor in Human Pulmonary Artery Smooth Muscle.

Hartman W, Helan M, Smelter D, Sathish V, Thompson M, Pabelick CM, Johnson B, Prakash YS - PLoS ONE (2015)

BDNF/TrkB in hypoxia effects on PASMC survival.Western blots for pPI3k, pAkt, and pERK in denuded human PA (aand b). After 24 hr hypoxia exposure, PI3 kinase (c) and pAkt/Akt (d) levels were both increased: effects blunted by BDNF neutralization or HIF1α inhibition. In normoxia, 100 pM BDNF enhanced PI3 kinase expression and Akt phosphorylation. 24h hypoxia also enhanced phosphorylation of ERK1/2 (e). In normoxia, 100 pM BDNF enhanced ERK1/2 phosphorylation. Extracellular neutralization of BDNF using TrkB-Fc (1 μg/ml) or inhibition of HIF1α blunted hypoxia effects on ERK phosphorylation. Values are means ± SE (n = 3 patients). *Significant difference from normoxia control; # significant inhibitor effect from hypoxia control (p<0.05).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4507987&req=5

pone.0129489.g005: BDNF/TrkB in hypoxia effects on PASMC survival.Western blots for pPI3k, pAkt, and pERK in denuded human PA (aand b). After 24 hr hypoxia exposure, PI3 kinase (c) and pAkt/Akt (d) levels were both increased: effects blunted by BDNF neutralization or HIF1α inhibition. In normoxia, 100 pM BDNF enhanced PI3 kinase expression and Akt phosphorylation. 24h hypoxia also enhanced phosphorylation of ERK1/2 (e). In normoxia, 100 pM BDNF enhanced ERK1/2 phosphorylation. Extracellular neutralization of BDNF using TrkB-Fc (1 μg/ml) or inhibition of HIF1α blunted hypoxia effects on ERK phosphorylation. Values are means ± SE (n = 3 patients). *Significant difference from normoxia control; # significant inhibitor effect from hypoxia control (p<0.05).
Mentions: Hypoxia has been previously shown to enhance PASMC survival and proliferation,[10,11,41] acting through pathways such as pPI3K and pAkt/Akt [25,42,43] which happen to overlap with BDNF signaling.[25] Representative Western blots are shown in Fig 5A and 5B. Following BDNF exposure in either normoxia or hypoxia, enhanced pPI3K and pERK until approximately 30 minutes of BDNF treatment were noted. No short term enhancement of pAkt was observed with BDNF. At 24h, however, (Fig 5B) enhanced phospho-protein expression was observed in the presence of BDNF, particularly pPI3K (Fig 5B) and pAkt (Fig 5C). Hypoxia alone also upregulated expression of these proteins. While the additional presence of BDNF did not further enhance pPI3K or pAkt/Akt levels in hypoxia, both the HIF1α inhibitor, and TrkB-Fc reduced expression of these pro-survival proteins in hypoxia exposed tissues (Fig 5B and 5C; n = 3 for each group; p<0.05 for BDNF, HIF1α inhibitor and TrkB-Fc).

Bottom Line: Recent studies suggest that growth factors called neurotrophins, particularly brain-derived neurotrophic factor (BDNF), can influence lung structure and function, and their role in the pulmonary artery warrants further investigation.In arteries of patients with pulmonary hypertension, BDNF expression and release was higher at baseline.Accordingly, the BDNF-TrkB system could be a key player in the pathogenesis of hypoxia-induced pulmonary vascular diseases, and thus a potential target for therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota, 55905, United States of America.

ABSTRACT

Background: Hypoxia effects on pulmonary artery structure and function are key to diseases such as pulmonary hypertension. Recent studies suggest that growth factors called neurotrophins, particularly brain-derived neurotrophic factor (BDNF), can influence lung structure and function, and their role in the pulmonary artery warrants further investigation. In this study, we examined the effect of hypoxia on BDNF in humans, and the influence of hypoxia-enhanced BDNF expression and signaling in human pulmonary artery smooth muscle cells (PASMCs).

Methods and results: 48h of 1% hypoxia enhanced BDNF and TrkB expression, as well as release of BDNF. In arteries of patients with pulmonary hypertension, BDNF expression and release was higher at baseline. In isolated PASMCs, hypoxia-induced BDNF increased intracellular Ca2+ responses to serotonin: an effect altered by HIF1α inhibition or by neutralization of extracellular BDNF via chimeric TrkB-Fc. Enhanced BDNF/TrkB signaling increased PASMC survival and proliferation, and decreased apoptosis following hypoxia.

Conclusions: Enhanced expression and signaling of the BDNF-TrkB system in PASMCs is a potential mechanism by which hypoxia can promote changes in pulmonary artery structure and function. Accordingly, the BDNF-TrkB system could be a key player in the pathogenesis of hypoxia-induced pulmonary vascular diseases, and thus a potential target for therapy.

No MeSH data available.


Related in: MedlinePlus