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GDF-15 is abundantly expressed in plexiform lesions in patients with pulmonary arterial hypertension and affects proliferation and apoptosis of pulmonary endothelial cells.

Nickel N, Jonigk D, Kempf T, Bockmeyer CL, Maegel L, Rische J, Laenger F, Lehmann U, Sauer C, Greer M, Welte T, Hoeper MM, Golpon HA - Respir. Res. (2011)

Bottom Line: The effects of GDF-15 on the proliferation and cell death of HPMEC were studied using recombinant GDF-15 protein.GDF-15 expression was found to be increased in lung specimens from PAH patients, compared to normal lungs.Apoptotic cell death of HPMEC was diminished, whereas HPMEC proliferation was either increased or decreased depending of the concentration of recombinant GDF-15 protein.

View Article: PubMed Central - HTML - PubMed

Affiliation: Clinic for Pulmonary Medicine, Hannover Medical School, Hannover, Germany.

ABSTRACT

Background: Growth-differentiation factor-15 (GDF-15) is a stress-responsive, transforming growth factor-β-related cytokine, which has recently been reported to be elevated in serum of patients with idiopathic pulmonary arterial hypertension (IPAH). The aim of the study was to examine the expression and biological roles of GDF-15 in the lung of patients with pulmonary arterial hypertension (PAH).

Methods: GDF-15 expression in normal lungs and lung specimens of PAH patients were studied by real-time RT-PCR and immunohistochemistry. Using laser-assisted micro-dissection, GDF-15 expression was further analyzed within vascular compartments of PAH lungs. To elucidate the role of GDF-15 on endothelial cells, human pulmonary microvascular endothelial cells (HPMEC) were exposed to hypoxia and laminar shear stress. The effects of GDF-15 on the proliferation and cell death of HPMEC were studied using recombinant GDF-15 protein.

Results: GDF-15 expression was found to be increased in lung specimens from PAH patients, compared to normal lungs. GDF-15 was abundantly expressed in pulmonary vascular endothelial cells with a strong signal in the core of plexiform lesions. HPMEC responded with marked upregulation of GDF-15 to hypoxia and laminar shear stress. Apoptotic cell death of HPMEC was diminished, whereas HPMEC proliferation was either increased or decreased depending of the concentration of recombinant GDF-15 protein.

Conclusions: GDF-15 expression is increased in PAH lungs and appears predominantly located in vascular endothelial cells. The expression pattern as well as the observed effects on proliferation and apoptosis of pulmonary endothelial cells suggest a role of GDF-15 in the homeostasis of endothelial cells in PAH patients.

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Upregulation of GDF-15 by hypoxia in endothelial cells. Human pulmonary microvascular endothelial cells (HPMEC) were subjected to hypoxia for various time periods (2 h to 24 h). The mRNA and protein levels of GDF-15 (secreted form) were determined either by quantitative RT-PCR (panel A), immunoradiometric sandwich assay - IRMA (panel B) or Western Blot analysis (panel C). Hypoxia increased GDF-15 expression in a time dependent manner, which was initially detected after 2 hours on mRNA level and after 4 hours on protein level. Data from n = 4 each group are shown as mean ± SD. *p < 0.05 compared to control.
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Figure 9: Upregulation of GDF-15 by hypoxia in endothelial cells. Human pulmonary microvascular endothelial cells (HPMEC) were subjected to hypoxia for various time periods (2 h to 24 h). The mRNA and protein levels of GDF-15 (secreted form) were determined either by quantitative RT-PCR (panel A), immunoradiometric sandwich assay - IRMA (panel B) or Western Blot analysis (panel C). Hypoxia increased GDF-15 expression in a time dependent manner, which was initially detected after 2 hours on mRNA level and after 4 hours on protein level. Data from n = 4 each group are shown as mean ± SD. *p < 0.05 compared to control.

Mentions: HPMEC were exposed to hypoxia for various time periods. mRNA and protein levels for GDF-15 were determined using quantitative RT-PCR (Figure 9, panel A), IRMA (Figure 9, panel B) and Western Blot analysis (Figure 9, panel C). Hypoxia increased GDF-15 expres-sion in a time-dependent manner, which was initially detected after 2 hours at mRNA level and after 4 hours at protein level. After 10 hours there was a 12-fold upregulation of GDF-15 mRNA. Western Blot analysis from HPMEC exposed to hypoxia showed a strong upregulation of the secreted 30 kDa form of GDF-15. To assess the effects of shear stress on the mRNA expression of GDF-15, HPMEC were exposed to laminar flow (5 and 15 dynes/cm2) for 6 h in a cone-and-plate apparatus. Laminar shear stress (5 dynes/cm2) resulted in a 2-fold upregulation of GDF-15 transcripts compared to static controls (0 dynes/cm2). By increasing the laminar flow to 15 dynes/cm2, a 10-fold upregulation of GDF-15 mRNA was noted (Figure 10).


GDF-15 is abundantly expressed in plexiform lesions in patients with pulmonary arterial hypertension and affects proliferation and apoptosis of pulmonary endothelial cells.

Nickel N, Jonigk D, Kempf T, Bockmeyer CL, Maegel L, Rische J, Laenger F, Lehmann U, Sauer C, Greer M, Welte T, Hoeper MM, Golpon HA - Respir. Res. (2011)

Upregulation of GDF-15 by hypoxia in endothelial cells. Human pulmonary microvascular endothelial cells (HPMEC) were subjected to hypoxia for various time periods (2 h to 24 h). The mRNA and protein levels of GDF-15 (secreted form) were determined either by quantitative RT-PCR (panel A), immunoradiometric sandwich assay - IRMA (panel B) or Western Blot analysis (panel C). Hypoxia increased GDF-15 expression in a time dependent manner, which was initially detected after 2 hours on mRNA level and after 4 hours on protein level. Data from n = 4 each group are shown as mean ± SD. *p < 0.05 compared to control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3113721&req=5

Figure 9: Upregulation of GDF-15 by hypoxia in endothelial cells. Human pulmonary microvascular endothelial cells (HPMEC) were subjected to hypoxia for various time periods (2 h to 24 h). The mRNA and protein levels of GDF-15 (secreted form) were determined either by quantitative RT-PCR (panel A), immunoradiometric sandwich assay - IRMA (panel B) or Western Blot analysis (panel C). Hypoxia increased GDF-15 expression in a time dependent manner, which was initially detected after 2 hours on mRNA level and after 4 hours on protein level. Data from n = 4 each group are shown as mean ± SD. *p < 0.05 compared to control.
Mentions: HPMEC were exposed to hypoxia for various time periods. mRNA and protein levels for GDF-15 were determined using quantitative RT-PCR (Figure 9, panel A), IRMA (Figure 9, panel B) and Western Blot analysis (Figure 9, panel C). Hypoxia increased GDF-15 expres-sion in a time-dependent manner, which was initially detected after 2 hours at mRNA level and after 4 hours at protein level. After 10 hours there was a 12-fold upregulation of GDF-15 mRNA. Western Blot analysis from HPMEC exposed to hypoxia showed a strong upregulation of the secreted 30 kDa form of GDF-15. To assess the effects of shear stress on the mRNA expression of GDF-15, HPMEC were exposed to laminar flow (5 and 15 dynes/cm2) for 6 h in a cone-and-plate apparatus. Laminar shear stress (5 dynes/cm2) resulted in a 2-fold upregulation of GDF-15 transcripts compared to static controls (0 dynes/cm2). By increasing the laminar flow to 15 dynes/cm2, a 10-fold upregulation of GDF-15 mRNA was noted (Figure 10).

Bottom Line: The effects of GDF-15 on the proliferation and cell death of HPMEC were studied using recombinant GDF-15 protein.GDF-15 expression was found to be increased in lung specimens from PAH patients, compared to normal lungs.Apoptotic cell death of HPMEC was diminished, whereas HPMEC proliferation was either increased or decreased depending of the concentration of recombinant GDF-15 protein.

View Article: PubMed Central - HTML - PubMed

Affiliation: Clinic for Pulmonary Medicine, Hannover Medical School, Hannover, Germany.

ABSTRACT

Background: Growth-differentiation factor-15 (GDF-15) is a stress-responsive, transforming growth factor-β-related cytokine, which has recently been reported to be elevated in serum of patients with idiopathic pulmonary arterial hypertension (IPAH). The aim of the study was to examine the expression and biological roles of GDF-15 in the lung of patients with pulmonary arterial hypertension (PAH).

Methods: GDF-15 expression in normal lungs and lung specimens of PAH patients were studied by real-time RT-PCR and immunohistochemistry. Using laser-assisted micro-dissection, GDF-15 expression was further analyzed within vascular compartments of PAH lungs. To elucidate the role of GDF-15 on endothelial cells, human pulmonary microvascular endothelial cells (HPMEC) were exposed to hypoxia and laminar shear stress. The effects of GDF-15 on the proliferation and cell death of HPMEC were studied using recombinant GDF-15 protein.

Results: GDF-15 expression was found to be increased in lung specimens from PAH patients, compared to normal lungs. GDF-15 was abundantly expressed in pulmonary vascular endothelial cells with a strong signal in the core of plexiform lesions. HPMEC responded with marked upregulation of GDF-15 to hypoxia and laminar shear stress. Apoptotic cell death of HPMEC was diminished, whereas HPMEC proliferation was either increased or decreased depending of the concentration of recombinant GDF-15 protein.

Conclusions: GDF-15 expression is increased in PAH lungs and appears predominantly located in vascular endothelial cells. The expression pattern as well as the observed effects on proliferation and apoptosis of pulmonary endothelial cells suggest a role of GDF-15 in the homeostasis of endothelial cells in PAH patients.

Show MeSH
Related in: MedlinePlus