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Ascorbate protects endothelial barrier function during septic insult: Role of protein phosphatase type 2A
Authors:Min Han  Suresh Pendem  Suet Ling Teh  Dinesh K Sukumaran  Feng Wu  John X Wilson
Institution:1. Bordeaux University Hospital, F-33000 Bordeaux, France;2. Univ. Bordeaux, L’Institut de RYthmologie et de modelisation Cardiaque, Centre de recherche Cardio-Thoracique de Bordeaux, U1045, F-33000, Bordeaux, France;3. University of Witten/Herdecke, Medical Center Porz am Rhein, Cologne, Germany
Abstract:Endothelial barrier dysfunction contributes to morbidity in sepsis. We tested the hypothesis that raising the intracellular ascorbate concentration protects the endothelial barrier from septic insult by inhibiting protein phosphatase type 2A. Monolayer cultures of microvascular endothelial cells were incubated with ascorbate, dehydroascorbic acid (DHAA), the NADPH oxidase inhibitors apocynin and diphenyliodonium, or the PP2A inhibitor okadaic acid and then were exposed to septic insult (lipopolysaccharide and interferon-γ). Under standard culture conditions that depleted intracellular ascorbate, septic insult stimulated oxidant production and PP2A activity, dephosphorylated phosphoserine and phosphothreonine residues in the tight junction-associated protein occludin, decreased the abundance of occludin at cell borders, and increased monolayer permeability to albumin. NADPH oxidase inhibitors prevented PP2A activation and monolayer leak, showing that these changes required reactive oxygen species. Okadaic acid, at a concentration that inhibited PP2A activity and monolayer leak, prevented occludin dephosphorylation and redistribution, implicating PP2A in the response of occludin to septic insult. Incubation with ascorbate or DHAA raised intracellular ascorbate concentrations and mitigated the effects of septic insult. In conclusion, ascorbate acts within microvascular endothelial cells to inhibit septic stimulation of oxidant production by NADPH oxidase and thereby prevents PP2A activation, PP2A-dependent dephosphorylation and redistribution of occludin, and disruption of the endothelial barrier.
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