Abstract
Growth differentiation factor 15 (GDF15), a direct target gene of p53, is a multifunctional member of the TGF-β/BMP superfamily. GDF15 can be induced and is implicated as a key secretory cytokine in response to multiple cellular stimuli. Accumulating evidence indicates that GDF15 is associated with the development and prognosis of diabetes mellitus, while whether GDF15 can be induced by high glucose is unknown. In the present study, we revealed that high glucose could induce GDF15 expression and secretion in cultured human umbilical vein endothelial cells in a ROS- and p53-dependent manner. Inhibition of high glucose-induced GDF15 expression by siRNA demonstrated that adaptively induced GDF15 played a protective role against high glucose-induced human umbilical vein endothelial cell apoptosis via maintaining the active state of PI3K/Akt/eNOS pathway and attenuating NF-κB/JNK pathway activation. The protective effects of GDF15 were probably achieved by inhibiting ROS overproduction in high glucose-treated human umbilical vein endothelial cells in a negative feedback manner. Our results suggest that high glucose can promote GDF15 expression and secretion in human umbilical vein endothelial cells, which in turn attenuates high glucose-induced endothelial cell apoptosis.
Highlights
Growth differentiation factor 15 (GDF15), known as macrophage inhibiting cytokine 1 (MIC-1) [1] [2], placental transformation growth factor (PTGF-b) [3] [4] [5], prostate derived factor (PDF) [6], placental bone morphogenetic protein (PLAB) [7] [8], nonsteroidal antiinflammatory drugs (NSAID) activated gene-1 (NAG-1) [9] [10], PL74 [11], is a multifunctional member of the transforming growth factor beta (TGF-b)/bone morphogenetic protein (BMP) superfamily, which is involved in the regulation of cell proliferation, differentiation, apoptosis, inflammation, and tumorigenesis
The ELISA assay showed that secreted GDF15 in the culture medium increased at 24 and 48 h (Fig. 1 C). These results demonstrate that high glucose can induce GDF15 expression and secretion in Human umbilical venous endothelial cells (HUVECs) cells in a timedependent manner
We discovered that high glucose could induce GDF15 expression and secretion in HUVEC cells in a reactive oxygen species (ROS)- and p53-dependent manner
Summary
Growth differentiation factor 15 (GDF15), known as macrophage inhibiting cytokine 1 (MIC-1) [1] [2], placental transformation growth factor (PTGF-b) [3] [4] [5], prostate derived factor (PDF) [6], placental bone morphogenetic protein (PLAB) [7] [8], NSAID activated gene-1 (NAG-1) [9] [10], PL74 [11], is a multifunctional member of the transforming growth factor beta (TGF-b)/bone morphogenetic protein (BMP) superfamily, which is involved in the regulation of cell proliferation, differentiation, apoptosis, inflammation, and tumorigenesis. The etiology of diabetic atherosclerosis includes the increase of reactive oxygen species (ROS) and the decrease of nitric oxide (NO) bioavailability in endothelial cells as a result of high glucose level [22]. ROS can function as signaling molecules and participate in the regulation of cell activities at lower concentrations, but at higher concentrations ROS can induce oxidative stress that causes cellular injury and death [23] [24]. Much evidence implicates that high glucose-induced apoptosis in human endothelial cells is associated with increased ROS concentrations and subsequent triggered multiple signaling pathways [25] [26] [27] [28] [29] [30] [31]
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