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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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GDF-15 mRNA expression in normal human lung. GDF-15 mRNA expression in normal lung and lung tissue from patients with pulmonary arterial hypertension (PAH) was assessed by real-time RT-PCR. Data are presented as relative expression of GDF-15 mRNA normalized to two housekeeping genes. Data from n = 5 each group are shown as mean ± SD. * = p < 0.05 vs. normal lung.
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Figure 1: GDF-15 mRNA expression in normal human lung. GDF-15 mRNA expression in normal lung and lung tissue from patients with pulmonary arterial hypertension (PAH) was assessed by real-time RT-PCR. Data are presented as relative expression of GDF-15 mRNA normalized to two housekeeping genes. Data from n = 5 each group are shown as mean ± SD. * = p < 0.05 vs. normal lung.

Mentions: GDF-15 mRNA expression in whole lung tissue was assessed using real-time RT-PCR. Com-pared to normal lung tissue, GDF-15 expression was 5-fold increased in lung tissue from PAH patients (Figure 1). To assess protein expression of GDF-15 in human lung we performed immunohistochem-istry studies. In normal lung, GDF-15 was noted in endothelial cells of small pulmonary arteries as well as in alveolar macrophages (Figure 2). Smooth muscle cells and epithelial cells exhibited only a weak signal. In PAH lungs GDF-15 protein expression was observed in the endothelial cell layers of pulmonary arteries with medial hypertrophy, whereas little or no GDF-15 protein expression could be detected in the smooth muscle cells of remodeled pulmonary arteries (Figure 3). In concentric lesions GDF-15 expression was noted in cells lining the small lumen of lesions, probably endothelial cells (Figure 4). In plexiform lesions, an intense signal for GDF-15 protein was observed in the cells lining the vascular channels (Figure 5). There were no differences in the cellular expression pattern of GDF-15 in IPAH (Figure 5) and PAH due to Eisenmenger's physiology (Figure 6). As a negative control we used a rabbit IgG isotype control which was lacking a staining signal (Figure 7). To confirm the GDF-15 expres-sion patterns seen in the immunohistochemistry studies, laser-assisted micro-dissections of vascular compart-ments from normal lungs and PAH lungs were performed (Figure 8). Transcripts for GDF-15 were amplified from laser-captured vascular cells of normal pulmonary arteries and plexiform lesions of PAH patients by using quantitative RT-PCR. Compared to normal pulmonary arteries, a 3-fold increase of GDF-15 transcripts was detected in plexiform lesions of patients with PAH. To study the cellular composition of plexiform lesions, transcripts for the endothelial cell marker CD31 and eNOs as well as the smooth muscle cell marker myosin heavy chain were also amplified from microdissected vascular cells (Additional file 3). Compared to the vessel wall of normal arteries expression of CD31 and eNOS was increased in plexiform lesions. On the other hand, the smooth muscle cell marker myosin heavy chain was also expressed in microdissected cells from plexiform lesions suggesting a heterogenous cellular composition of these vascular structures.


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)

GDF-15 mRNA expression in normal human lung. GDF-15 mRNA expression in normal lung and lung tissue from patients with pulmonary arterial hypertension (PAH) was assessed by real-time RT-PCR. Data are presented as relative expression of GDF-15 mRNA normalized to two housekeeping genes. Data from n = 5 each group are shown as mean ± SD. * = p < 0.05 vs. normal lung.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: GDF-15 mRNA expression in normal human lung. GDF-15 mRNA expression in normal lung and lung tissue from patients with pulmonary arterial hypertension (PAH) was assessed by real-time RT-PCR. Data are presented as relative expression of GDF-15 mRNA normalized to two housekeeping genes. Data from n = 5 each group are shown as mean ± SD. * = p < 0.05 vs. normal lung.
Mentions: GDF-15 mRNA expression in whole lung tissue was assessed using real-time RT-PCR. Com-pared to normal lung tissue, GDF-15 expression was 5-fold increased in lung tissue from PAH patients (Figure 1). To assess protein expression of GDF-15 in human lung we performed immunohistochem-istry studies. In normal lung, GDF-15 was noted in endothelial cells of small pulmonary arteries as well as in alveolar macrophages (Figure 2). Smooth muscle cells and epithelial cells exhibited only a weak signal. In PAH lungs GDF-15 protein expression was observed in the endothelial cell layers of pulmonary arteries with medial hypertrophy, whereas little or no GDF-15 protein expression could be detected in the smooth muscle cells of remodeled pulmonary arteries (Figure 3). In concentric lesions GDF-15 expression was noted in cells lining the small lumen of lesions, probably endothelial cells (Figure 4). In plexiform lesions, an intense signal for GDF-15 protein was observed in the cells lining the vascular channels (Figure 5). There were no differences in the cellular expression pattern of GDF-15 in IPAH (Figure 5) and PAH due to Eisenmenger's physiology (Figure 6). As a negative control we used a rabbit IgG isotype control which was lacking a staining signal (Figure 7). To confirm the GDF-15 expres-sion patterns seen in the immunohistochemistry studies, laser-assisted micro-dissections of vascular compart-ments from normal lungs and PAH lungs were performed (Figure 8). Transcripts for GDF-15 were amplified from laser-captured vascular cells of normal pulmonary arteries and plexiform lesions of PAH patients by using quantitative RT-PCR. Compared to normal pulmonary arteries, a 3-fold increase of GDF-15 transcripts was detected in plexiform lesions of patients with PAH. To study the cellular composition of plexiform lesions, transcripts for the endothelial cell marker CD31 and eNOs as well as the smooth muscle cell marker myosin heavy chain were also amplified from microdissected vascular cells (Additional file 3). Compared to the vessel wall of normal arteries expression of CD31 and eNOS was increased in plexiform lesions. On the other hand, the smooth muscle cell marker myosin heavy chain was also expressed in microdissected cells from plexiform lesions suggesting a heterogenous cellular composition of these vascular structures.

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