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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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Effect of GDF-15 on endothelial cell proliferation and sprouting. Proliferation of human pulmonary microvascular endothelial (HPMEC) cell was assessed using a rapid colorimetric proliferation assay. At a concentration of 5 ng/ml recombinant GDF-15 led to increased HPMEC proliferation (panel A), whereas a reduction of HPMEC proliferation (panel B) was seen at higher concentration of GDF-15 (50 ng/ml). Data from n = 5 each group are shown as mean ± SD. * = p < 0.05 vs. control. Sprouting of human pulmonary microvascular endothelial cells (HPMEC) was assessed using a three-dimensional spheroid sprouting assay. Compared to control (panel C), recombinant GDF-15 protein at a concentration of 5 ng/ml increased endothelial cell sprouting (panel D), whereas at higher concentrations (50 ng/ml) sprouting was decreased (panel E). Five spheroids per group and per experiment were analyzed.
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Figure 11: Effect of GDF-15 on endothelial cell proliferation and sprouting. Proliferation of human pulmonary microvascular endothelial (HPMEC) cell was assessed using a rapid colorimetric proliferation assay. At a concentration of 5 ng/ml recombinant GDF-15 led to increased HPMEC proliferation (panel A), whereas a reduction of HPMEC proliferation (panel B) was seen at higher concentration of GDF-15 (50 ng/ml). Data from n = 5 each group are shown as mean ± SD. * = p < 0.05 vs. control. Sprouting of human pulmonary microvascular endothelial cells (HPMEC) was assessed using a three-dimensional spheroid sprouting assay. Compared to control (panel C), recombinant GDF-15 protein at a concentration of 5 ng/ml increased endothelial cell sprouting (panel D), whereas at higher concentrations (50 ng/ml) sprouting was decreased (panel E). Five spheroids per group and per experiment were analyzed.

Mentions: To investigate the angiogenic effects of GDF-15 on HPMEC proliferation, a rapid colorimetric proliferation assay was performed [29]. At a concentration of 5 ng/ml recombinant GDF-15 protein significantly increased endothelial cell proliferation at different time points ranging from 12 h to 48 h (Figure 11, panel A). Whereas 50 ng/ml recombinant GDF-15 incubated for 6 to 48 hours showed a significant inhibition of endothelial cell proliferation (Figure 11, panel B).


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)

Effect of GDF-15 on endothelial cell proliferation and sprouting. Proliferation of human pulmonary microvascular endothelial (HPMEC) cell was assessed using a rapid colorimetric proliferation assay. At a concentration of 5 ng/ml recombinant GDF-15 led to increased HPMEC proliferation (panel A), whereas a reduction of HPMEC proliferation (panel B) was seen at higher concentration of GDF-15 (50 ng/ml). Data from n = 5 each group are shown as mean ± SD. * = p < 0.05 vs. control. Sprouting of human pulmonary microvascular endothelial cells (HPMEC) was assessed using a three-dimensional spheroid sprouting assay. Compared to control (panel C), recombinant GDF-15 protein at a concentration of 5 ng/ml increased endothelial cell sprouting (panel D), whereas at higher concentrations (50 ng/ml) sprouting was decreased (panel E). Five spheroids per group and per experiment were analyzed.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 11: Effect of GDF-15 on endothelial cell proliferation and sprouting. Proliferation of human pulmonary microvascular endothelial (HPMEC) cell was assessed using a rapid colorimetric proliferation assay. At a concentration of 5 ng/ml recombinant GDF-15 led to increased HPMEC proliferation (panel A), whereas a reduction of HPMEC proliferation (panel B) was seen at higher concentration of GDF-15 (50 ng/ml). Data from n = 5 each group are shown as mean ± SD. * = p < 0.05 vs. control. Sprouting of human pulmonary microvascular endothelial cells (HPMEC) was assessed using a three-dimensional spheroid sprouting assay. Compared to control (panel C), recombinant GDF-15 protein at a concentration of 5 ng/ml increased endothelial cell sprouting (panel D), whereas at higher concentrations (50 ng/ml) sprouting was decreased (panel E). Five spheroids per group and per experiment were analyzed.
Mentions: To investigate the angiogenic effects of GDF-15 on HPMEC proliferation, a rapid colorimetric proliferation assay was performed [29]. At a concentration of 5 ng/ml recombinant GDF-15 protein significantly increased endothelial cell proliferation at different time points ranging from 12 h to 48 h (Figure 11, panel A). Whereas 50 ng/ml recombinant GDF-15 incubated for 6 to 48 hours showed a significant inhibition of endothelial cell proliferation (Figure 11, panel B).

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