Nicotine increases plasminogen activator inhibitor-1 production by human brain endothelial cells via protein kinase C-associated pathway

• Published in: Stroke (1970) 1999-03, Vol.30 (3), p.651-655
• Main Authors: Zidovetzki, R, Chen, P, Fisher, M, Hofman, F M, Faraci, F M
• Format: Article
• Language: English
• Subjects: Adult; Brain - cytology; Brain - drug effects; Brain - metabolism; Cells, Cultured; Endothelium - metabolism; Humans; Nicotine - pharmacology; Plasminogen Activator Inhibitor 1 - biosynthesis; Protein Kinase C - metabolism
• ISSN: 0039-2499; 1524-4628
• DOI: 10.1161/01.str.30.3.651

Smoking both increases stroke risk and reduces the risk of thrombolysis-associated intracerebral hemorrhage. Plasminogen activator inhibitor-1 (PAI-1) is a major regulator of fibrinolysis; elevation of PAI-1 is associated with an increased risk of thrombotic disorders. We studied the effect of nicotine, an important constituent of cigarette smoke, on PAI-1 production by human brain endothelial cells. Adult human central nervous system endothelial cells (CNS-EC) were used for tissue culture experiments. We analyzed culture supernatant for PAI-1 protein and measured PAI-1 mRNA (by Northern blot analysis) and protein kinase C (PK-C) activity. Nicotine at 100 nmol/L increased PAI-1 protein production and mRNA expression by CNS-EC. After 72 hours of exposure to nicotine, the concentration of secreted PAI-1 in the cell supernatant was increased 1.90+/-0.2 fold compared with untreated cells. PAI-1 mRNA also increased approximately twofold. Inhibition of PK-C completely abolished this effect. Nicotine had no effect on the concentration of tissue plasminogen activator. Nicotine increases brain endothelial cell PAI-1 mRNA expression and protein production via PK-C-dependent pathway. These findings provide new insights into why smoking may be associated with predisposition to thrombosis and inversely associated with intracerebral hemorrhage after therapeutic tissue plasminogen activator therapy.