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

Abstract

BackgroundGrowth-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).MethodsGDF-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.ResultsGDF-15 expression was found to be increased in lung specimens from PAH patients, com-pared 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.ConclusionsGDF-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.

Lung fibroblasts accelerate wound closure in human alveolar epithelial cells through hepatocyte growth factor/c-Met signaling

“…We excluded IGF binding proteins from this experiment because they are binding proteins for IGFs. We tested these growth factors at a concentration of 10 ng/ml according to published papers (1,22,25,27,29,42,51).…”

“…A surprising finding was that among all the factors tested, only HGF significantly accelerated the wound closure in human AEC monolayers. Other factors, such as bFGF, BMP-5, FGF-4, KGF, FGF-10, GDF-15, IGF-1, OPG, and VEGF, which are known to be associated with cell proliferation, wound closure, and/or inflammation in the cells from the different organs, had no apparent effect on wound closure (1,19,22,25,27,29,42,51). These soluble factors are likely important in other organs or species, which could have different levels of receptors and receptor activation.…”

Growth differentiation factor-15 in children and adolescents with thalassemia intermedia: Relation to subclinical atherosclerosis and pulmonary vasculopathy

“…GDF-15 staining was observed in pulmonary vessels of all sizes, beginning from the microvasculature up to large pulmonary vessels and particularly in the intima of pulmonary arteries [10]. Hypoxia is a potent stimulator of GDF-15 expression in pulmonary endothelial cells.…”

“…Under normal conditions, GDF-15 is only weakly expressed in most tissues [8]. However GDF-15 is strongly upregulated in disease states such as acute injury, tissue hypoxia, inflammation and oxidative stress [9,10].…”

Targets of anti-endothelial cell antibodies in pulmonary hypertension and scleroderma

“…As our study is descriptive and did not aim to establish a correlation between autoantibody reactivity and disease evolution, further studies are needed to document whether AECAs might help to characterise a subgroup of SSc patients at higher risk of developing vascular complications and whether AECAs might, therefore, be considered as a predictor of outcome in SSc patients. In iPAH, where disorganised proliferation and apoptosis of EC are observed [28] and lead to the formation of plexiform lesions, it would be important to investigate the role of AECAs.…”