Abstract
Glucose-6-phosphate dehydrogenase (G6PD) deficiency, the most common genetic inherited trait among humans, affects ~7% of the global population, and is associated with excess risk of cardiovascular disease (CVD). Transforming growth factor-β (TGF-β) regulates immune function, proliferation, epithelial-mesenchymal transition, fibrosis, cancer, and vascular dysfunction. This study examined whether G6PD deficiencies can alter TGF-β-mediated NADPH oxidases (NOX) and cell adhesion molecules (CAM) in human aortic endothelial cells (HAEC). Results show that treatment with high glucose and the saturated free fatty acid palmitate significantly downregulated G6PD; in contrast, mRNA levels of TGF-β components, NOX and its activity, and reactive oxygen species (ROS) were significantly upregulated in HAEC. The expression levels of TGF-β and its receptors, NOX and its activity, and ROS were significantly higher in HG-exposed G6PD-deficient cells (G6PD siRNA) compared to G6PD-normal cells. The protein levels of adhesion molecules (ICAM-1 and VCAM-1) and inflammatory cytokines (MCP-1 and TNF) were significantly increased in HG-exposed G6PD-deficient cells compared to G6PD-normal cells. The adherence of monocytes (SC cells) to HAEC was significantly elevated in HG-treated G6PD-deficient cells compared to control cells. Pharmacological inhibition of G6PD enhances ROS, NOX and its activity, and endothelial monocyte adhesion; these effects were impeded by NOX inhibitors. The inhibition of TGF-β prevents NOX2 and NOX4 mRNA expression and activity, ROS, and adhesion of monocytes to HAEC. L-Cysteine ethyl ester (cell-permeable) suppresses the mRNA levels of TGF-β and its receptors, along with NOX2 and NOX4, and decreases NOX activity, ROS, and adhesion of monocytes to HAEC. This suggests that G6PD deficiency promotes TGF-β/NADPH oxidases/ROS signaling, the expression of ICAM-1 and VCAM-1, and the adhesion of leukocytes to the endothelial monolayer, which can contribute to a higher risk for CVD.
Highlights
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common diverse X-linked human enzymopathy genetic trait [1]
Relative to the control and mannitol groups, high glucose and palmitate treated human aortic endothelial cells (HAEC) groups displayed impaired G6PD expression and activity (Figure S1A–C). This reduced activity of G6PD, which may contribute to increased oxidative stress, reduces glutathione content, upregulates mRNA levels of Transforming growth factor-β (TGF-β) components, and escalates NOX2/4 genes activity (Figure S1A,D–F)
Further metabolic insults facilitate increased monocyte-endothelial cell adhesion (Figure S1G,H). These results suggest that metabolic insults mediated G6PD deficiency leading to activation of the endothelium via the reactive oxygen species (ROS)/TGF-β/NADPH oxidases (NOX) system (Figure S1I)
Summary
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common diverse X-linked human enzymopathy genetic trait [1]. The prevalence and association between G6PD deficiency and the risk of CVD in the Mediterranean region were validated in a large cohort (9604) of a propensity score-matched study carried out in a large population from Northern Sardinia [5]. Another cross-sectional study in a Chinese population showed that 154917 G6PD-deficient females aged 20–49 had a higher risk for elevated blood pressure and hypertension during pre-pregnancy and pregnancy. They showed that G6PD deficiency was more obviously associated with elevated systolic blood pressure [6]
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