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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:1031.)
© 2004 American Heart Association, Inc.

Vascular Biology

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

Edgar A. Jaimes; Eugene G. DeMaster; Run-Xia Tian; Leopoldo Raij

From the Nephrology and Hypertension Section (E.A.J., R.-X.T.), Veterans Affairs Medical Center, Miami, Fla.; the Research Section (E.G.D.), Veterans Affairs Medical Center, Minneapolis, Minn.; and the Renal Division and Vascular Biology Institute (E.A.J., L.R.), University of Miami, Fla.

Correspondence to Edgar A. Jaimes, MD, VA Medical Center, 1201 NW 16th St, Nephrology Section Room A-1009, Miami, FL 33125. E-mail ejaimes{at}med.miami.edu

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<0.05 versus control), which was inhibited by the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitors diphenyleneiodinium, apocynin, and gp91 docking sequence-tat peptide but not by oxypurinol, the NO synthase inhibitor 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.

Exposure of pulmonary artery endothelial cells and pulmonary arteries to CSEs increased O

₂ production that was prevented by NADPH oxidase inhibition. Exposure to acrolein, a thiol-reactive agent found in CS, also increased endothelial O

₂ production. We conclude that stable thiol-reactive compounds in CS activate endothelial NADPH oxidase.

Key Words: nitric oxide • superoxide anion • cigarette smoke • NADPH oxidase • endothelium

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