Adaptive Induction of Growth Differentiation Factor 15 Attenuates Endothelial Cell Apoptosis in Response to High Glucose Stimulus

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.

GDF15 is a novel biomarker to evaluate efficacy of pyruvate therapy for mitochondrial diseases

“…GDF15 plays important roles in multiple pathologies including cardiovascular diseases, cancer, and inflammation. It has been shown that GDF15 is up-regulated by tumor suppressor p53 in response to high glucose or treatment with anti-cancer compounds (Baek et al, 2002;Li et al, 2013;Yang et al, 2003). The p53 protein is a transcription factor that responds to a variety of stresses such as DNA damage, oxidative stress, hypoxia, and metabolic stress, and it activates the expression of genes to induce cell cycle arrest, DNA repair, senescence, and cell death (Sermeus and Michiels, 2011;Sperka et al, 2012;Zhang et al, 2010).…”

Role of GDF15 (growth and differentiation factor 15) in pulmonary oxygen toxicity

“…It prevented low potassium induced death in cerebellar granule cells (Subramaniam et al, 2003) and had an anti-apoptotic effect on cultured cardiomyocytes, subjected to simulated ischemia/reperfusion and endothelial cells subjected to hypoxia (Kempf et al, 2006; Song et al, 2012) or high glucose stimulus (Li et al, 2013a). Agarwal et al showed that application of exogenous GDF-15 or its constitutive expression from a cDNA provided remarkable protection of p53-null cells from apoptosis mediated by phosphonacetyl-l-aspartate, which blocks the synthesis of pyrimidines (Agarwal et al, 2006).…”

Cardiac‐Secreted Factors as Peripheral Metabolic Regulators and Potential Disease Biomarkers

“…These results reinforce that GDF15 is an antihypertrophic factor. Other studies indicate that GDF‐15 is cardioprotective by activating the phosphoinositide 3‐kinase/AKT/endothelial nitric oxide synthase/NO pathway . In general, TGF‐β signaling activation was previously viewed as detrimental to cardiac function, resulting in cardiac remodeling, including hypertrophy and fibrosis.…”