Stable Compounds of Cigarette Smoke Induce Endothelial Superoxide Anion Production via NADPH Oxidase Activation

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Abstract
Objective— Endothelial dysfunction is an early manifestation of cigarette smoke (CS) toxicity. We have previously demonstrated that CS impairs nitric oxide (NO)-mediated endothelial function via increased generation of superoxide anion (O 2 ). In these studies, we investigated whether stable compounds present in CS activate specific pathways responsible for the increased endothelial O OV0254; 2 production. Methods and Results— Short exposure of bovine pulmonary artery endothelial cells (BPAECs), human pulmonary artery endothelial cells, and rat pulmonary arteries to CS extracts (CSEs) resulted in a large increase in O OV0254; 2 production (20-fold, 3-fold, and 2-fold increase, respectively; P N G -nitro- l -arginine methyl ester, or the mitochondrial respiration inhibitor rotenone. Exposure of BPAECs to acrolein, a stable thiol-reactive agent found in CS, increased O OV0254; 2 production 5-fold, which was prevented by prior inhibition of NADPH oxidase. Conclusions— These studies demonstrate that thiol-reactive stable compounds in CS can activate NADPH oxidase and increase endothelial O OV0254; 2 production, thereby reducing NO bioactivity and resulting in endothelial dysfunction. Clinically, these studies may contribute to the development of agents able to mitigate CS-mediated vascular toxicity.