title: Stable compounds of cigarette smoke induce endothelial superoxide anion production via NADPH oxidase activation.
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 (O2*). In these studies, we investigated whether stable compounds present in CS activate specific pathways responsible for the increased endothelial O2* production.
  
  
  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 O2* 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 O2* 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 O2* 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.
authors.affiliation: Nephrology and Hypertension Section, Veterans Affairs Medical Center, Miami, Fla 33125, USA. ejaimes@med.miami.edu
authors.forename: Edgar A
authors.initials: EA
authors.lastname: Jaimes
authors.forename: Eugene G
authors.initials: EG
authors.lastname: DeMaster
authors.forename: Run-Xia
authors.initials: RX
authors.lastname: Tian
authors.forename: Leopoldo
authors.initials: L
authors.lastname: Raij
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000171:Acrolein / Q000494:pharmacology; D000818:Animals; D002417:Cattle; D002478:Cells, Cultured / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D015696:Gene Products, tat / Q000494:pharmacology; D006801:Humans; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D009861:Onium Compounds / Q000494:pharmacology; D010117:Oxypurinol / Q000494:pharmacology; D011651:Pulmonary Artery / Q000166:cytology; D051381:Rats; D012402:Rotenone / Q000494:pharmacology; D012906:Smoke / Q000009:adverse effects / Q000032:analysis*; D013481:Superoxides / Q000378:metabolism*; D014026:Nicotiana / Q000737:chemistry*
chemical_list: D000098:Acetophenones; D015696:Gene Products, tat; D009861:Onium Compounds; D012906:Smoke; D012402:Rotenone; D013481:Superoxides; D009569:Nitric Oxide; C007517:diphenyleneiodonium; D000171:Acrolein; C056165:acetovanillone; D019255:NADPH Oxidases; D010117:Oxypurinol; D019331:NG-Nitroarginine Methyl Ester