Nicotine Increases Plasminogen Activator Inhibitor-1 Production by Human Brain Endothelial Cells via Protein Kinase C–Associated Pathway

Publisher Website
Google Scholar
Abstract
Background and Purpose —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. Methods —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. Results —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. Conclusions —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.

This publication has 42 references indexed in Scilit: