HMG-CoA reductase inhibitors reduce nicotine-induced expression of cellular adhesion molecules in cultured human coronary endothelial cells.
BACKGROUND
Smoking predisposes to the development of atherosclerosis and of its complications. The mechanisms responsible for these effects are not completely understood. We have investigated whether nicotine might promote a proatherosclerotic state in human coronary endothelial cells (HCAECs), studying the role of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in preventing these phenomena.


RESULTS
Real-time PCR showed that nicotine induced a dose-dependent increase in mRNA levels for vascular cellular adhesion molecule-1 (VCAM-1)/intercellular adhesion molecule-1 (ICAM-1). Fluorescent-activated cell sorting analysis showed that nicotine induced expression of functionally active VCAM-1/ICAM-1, since they increased leukocyte adherence to HCAECs. Oxygen free radicals, Rho A and nuclear factor kappaB (NF-kappaB) play a pivotal role in modulating these effects. Indeed, nicotine caused oxygen free radical production as well as activation of Rho A and NF-kappaB pathways, evaluated by malondialdehyde levels, pulldown assay and by electrophoretic mobility shift assay, respectively. Superoxide dimutase, Rho A (Y-27639) and NF-kappaB inhibitors (pyrrolidine dithiocarbamate ammonium, Bay 11-7082) suppressed nicotine effects on CAM expression. HMG-CoA reductase inhibitors prevented these nicotine-mediated effects by inhibiting free radical generation and by modulating activation of Rho A and NF-kappaB pathways.


CONCLUSIONS
Nicotine promotes CAM expression on HCAECs, shifting them toward a proatherosclerotic state. These effects might explain, at least in part, the deleterious cardiovascular consequences of cigarette smoking. HMG-CoA reductase inhibitors play an important role in preventing these phenomena.
Cirillo
Plinio
P
Division of Cardiology, University of Naples Federico II, Naples, Italy. pcirillo@unina.it
Pacileo
Mario
M
De Rosa
Salvatore
S
Calabrò
Paolo
P
Gargiulo
Annarita
A
Angri
Valeria
V
Prevete
Nella
N
Fiorentino
Isabella
I
Ucci
Grazia
G
Sasso
Laura
L
Petrillo
Gianluca
G
Musto D'Amore
Sergio
S
Chiariello
Massimo
M
D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D000077340:Fluvastatin; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D007211:Indoles / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D008148:Lovastatin / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D017035:Pravastatin / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D019821:Simvastatin / Q000494:pharmacology; D012907:Smoking / Q000009:adverse effects / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D016328:NF-kappa B; D018722:Nicotinic Agonists; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D000077340:Fluvastatin; D009538:Nicotine; D008148:Lovastatin; D019821:Simvastatin; D013482:Superoxide Dismutase; D011493:Protein Kinase C; D020742:rhoA GTP-Binding Protein; D017035:Pravastatin