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Glucose-6-Phosphate Dehydrogenase Deficiency Activates Endothelial Cell and Leukocyte Adhesion Mediated via the TGFβ/NADPH Oxidases/ROS Signaling Pathway

Department of Pediatrics and Center for Cardiovascular Diseases and Sciences, Louisiana State University Health Sciences Center-Shreveport, 1501 Kings Highway, Shreveport, LA 71130, USA
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Int. J. Mol. Sci. 2020, 21(20), 7474; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207474
Received: 4 September 2020 / Revised: 2 October 2020 / Accepted: 8 October 2020 / Published: 10 October 2020
(This article belongs to the Special Issue Endothelial Dysfunction: Pathophysiology and Molecular Mechanisms 2.0)
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. View Full-Text
Keywords: endothelial dysfunction; glucose-6-phosphate dehydrogenase deficiency; oxidative stress; transforming growth factor-beta; NADPH oxidase; reactive oxygen species; leukocyte adhesion; ICAM-1; VCAM-1 endothelial dysfunction; glucose-6-phosphate dehydrogenase deficiency; oxidative stress; transforming growth factor-beta; NADPH oxidase; reactive oxygen species; leukocyte adhesion; ICAM-1; VCAM-1
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MDPI and ACS Style

Parsanathan, R.; Jain, S.K. Glucose-6-Phosphate Dehydrogenase Deficiency Activates Endothelial Cell and Leukocyte Adhesion Mediated via the TGFβ/NADPH Oxidases/ROS Signaling Pathway. Int. J. Mol. Sci. 2020, 21, 7474. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207474

AMA Style

Parsanathan R, Jain SK. Glucose-6-Phosphate Dehydrogenase Deficiency Activates Endothelial Cell and Leukocyte Adhesion Mediated via the TGFβ/NADPH Oxidases/ROS Signaling Pathway. International Journal of Molecular Sciences. 2020; 21(20):7474. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207474

Chicago/Turabian Style

Parsanathan, Rajesh, and Sushil K. Jain 2020. "Glucose-6-Phosphate Dehydrogenase Deficiency Activates Endothelial Cell and Leukocyte Adhesion Mediated via the TGFβ/NADPH Oxidases/ROS Signaling Pathway" International Journal of Molecular Sciences 21, no. 20: 7474. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207474

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