on April 1, 2004
Published online before print April 1, 2004, doi: 10.1161/01.ATV.0000127083.88549.58
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Submitted on March 4, 2004
Accepted on March 18, 2004
Stable Compounds of Cigarette Smoke Induce Endothelial Superoxide Anion Production via NADPH Oxidase Activation
Edgar A. Jaimes *;
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.
* To whom correspondence should be addressed. 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. In these studies, we investigated whether stable compounds present in CS activate specific pathways responsible for the increased endothelial superoxide anion 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 superoxide anion 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 NG-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 superoxide anion 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 superoxide anion 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.
Key words: nitric oxide • superoxide anion • cigarette smoke • NADPH oxidase • endothelium
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