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

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 24; no. 6; pp. 1031 - 1036
• Main Authors: Jaimes, Edgar A, DeMaster, Eugene G, Tian, Run-Xia, Raij, Leopoldo
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.06.2004; Hagerstown, MD Lippincott
• Subjects: Acetophenones - pharmacology; Acrolein - pharmacology; Animals; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cattle; Cells, Cultured - drug effects; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Enzyme Activation - drug effects; Gene Products, tat - pharmacology; Humans; Medical sciences; NADPH Oxidases - antagonists & inhibitors; NADPH Oxidases - metabolism; NG-Nitroarginine Methyl Ester - pharmacology; Nicotiana - chemistry; Nitric Oxide - metabolism; Onium Compounds - pharmacology; Oxypurinol - pharmacology; Pulmonary Artery - cytology; Rats; Rotenone - pharmacology; Smoke - adverse effects; Smoke - analysis; Superoxides - metabolism; NADPH; Enzyme; Oxidase; Cardiovascular disease; Compounds; cigarette smoke; Endothelium; Vascular disease; Cigarette; Hyperoxides; Nitric oxide; NADPH oxidase; Atherosclerosis; Oxidoreductases; superoxide anion
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/01.ATV.0000127083.88549.58

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 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 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 sequencetat peptide but not by oxypurinol, the NO synthase inhibitor N-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 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 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.