Abstract
Venular hyperpermeability to macromolecules is a hallmark of inflammation. Platelet‐activating factor (PAF) is a pro‐inflammatory agent that increases permeability by stimulating endothelial nitric oxide synthase (eNOS) activity and nitric oxide (NO) production, which can either activate soluble guanylyl cyclase (sGC) and/or induce protein S‐nitrosation. Because the thioredoxin (Trx)/thioredoxin reductase (TrxR) system can reverse S‐nitrosation, we studied the significance of S‐nitrosation and the Trx/TrxR system on endothelial permeability in human microvascular endothelial cells (HMVEC) and in hamster cheek pouch microvascular endothelial cells (HCPMEC). We evaluated PAF‐induced protein S‐nitrosation using immunofluorescence, Trx/TrxR expression using immunofluorescence and western‐blot, and the efficacy of TrxR inhibitors on PAF‐induced hyperpermeability. PAF produces maximum protein S‐nitrosation at 1 and 15 min of stimulation. The Trx/TrxR system is expressed in HMVEC and HCPMEC. Inhibition of Trx/TrxR increased both basal and PAF‐stimulated permeability. Our results suggest an important role for the regulatory enzymes that control the levels of S‐nitrosation in the regulation of microvascular permeability. (Supported by NIH grants 5RO1 HL088479 and 5RO1 HL070634).
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