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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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Akt phosphorylation by GDF-15 in endothelial cells. GDF-15 induced Akt phosphorylation at Ser437 in human pulmonary microvascular endothelial cells (HPMEC). The cells were stimulated with recombinant GDF-15 protein (50 ng/ml) for 30 to 240 minutes. Akt and Ser437 were determined by immunoblotting. An exemplary blot from n = 3 experiments is presented.
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Figure 13: Akt phosphorylation by GDF-15 in endothelial cells. GDF-15 induced Akt phosphorylation at Ser437 in human pulmonary microvascular endothelial cells (HPMEC). The cells were stimulated with recombinant GDF-15 protein (50 ng/ml) for 30 to 240 minutes. Akt and Ser437 were determined by immunoblotting. An exemplary blot from n = 3 experiments is presented.

Mentions: HPMEC were exposed to hypoxia to induce apoptosis. In our hypoxia system the most prom-inent induction of apoptosis was observed after 8-12 hours. Apoptotic cell death was assessed by measuring the activities of caspases 3 and 7 (Figure 12, panel A), two of the key executioners of apoptosis, and by determining the number of Annexin V-positive/propidium iodide-negative cells (Figure 12, panel B). Recombinant GDF-15 protein at a concentration of either 5 or 50 ng/ml reduced hypoxia-induced apoptotic cell death. Stimulating HPMEC with recombinant GDF-15 protein (50 ng/ml) for 30 to 240 minutes resulted in an induction of Akt phosphorylation determined by immunoblotting (Figure 13).


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)

Akt phosphorylation by GDF-15 in endothelial cells. GDF-15 induced Akt phosphorylation at Ser437 in human pulmonary microvascular endothelial cells (HPMEC). The cells were stimulated with recombinant GDF-15 protein (50 ng/ml) for 30 to 240 minutes. Akt and Ser437 were determined by immunoblotting. An exemplary blot from n = 3 experiments is presented.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 13: Akt phosphorylation by GDF-15 in endothelial cells. GDF-15 induced Akt phosphorylation at Ser437 in human pulmonary microvascular endothelial cells (HPMEC). The cells were stimulated with recombinant GDF-15 protein (50 ng/ml) for 30 to 240 minutes. Akt and Ser437 were determined by immunoblotting. An exemplary blot from n = 3 experiments is presented.
Mentions: HPMEC were exposed to hypoxia to induce apoptosis. In our hypoxia system the most prom-inent induction of apoptosis was observed after 8-12 hours. Apoptotic cell death was assessed by measuring the activities of caspases 3 and 7 (Figure 12, panel A), two of the key executioners of apoptosis, and by determining the number of Annexin V-positive/propidium iodide-negative cells (Figure 12, panel B). Recombinant GDF-15 protein at a concentration of either 5 or 50 ng/ml reduced hypoxia-induced apoptotic cell death. Stimulating HPMEC with recombinant GDF-15 protein (50 ng/ml) for 30 to 240 minutes resulted in an induction of Akt phosphorylation determined by immunoblotting (Figure 13).

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