Stable compounds of cigarette smoke induce endothelial superoxide anion production via NADPH oxidase activation.
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.
Jaimes
Edgar A
EA
Nephrology and Hypertension Section, Veterans Affairs Medical Center, Miami, Fla 33125, USA. ejaimes@med.miami.edu
DeMaster
Eugene G
EG
Tian
Run-Xia
RX
Raij
Leopoldo
L
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*
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