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K+ channel blockers inhibit tissue factor expression by human monocytic cells
D J Crutchley1, L B Conanan, B G Que
1Miami Heart Research Institute, Miami Beach, Fla. 33140.
Circulation Research
|January 1, 1995
Summary
Potassium (K+) channel blockers, including 4-aminopyridine and tetraethylammonium chloride, significantly inhibit tissue factor (TF) expression in human monocytes stimulated by lipopolysaccharide (LPS). This suggests K+ channels play a key role in TF synthesis.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Human monocytes express tissue factor (TF), a procoagulant protein, upon stimulation by agents like bacterial lipopolysaccharide (LPS).
- Monocyte TF expression is implicated in intravascular coagulation during various disease states.
Purpose of the Study:
- To investigate the role of cellular K+ channels in regulating monocyte tissue factor (TF) expression.
- To determine if blocking K+ channels can inhibit LPS-induced TF expression in human monocytes.
Main Methods:
- Human peripheral blood monocytes and cultured THP-1 monocytic cells were stimulated with LPS.
- Tissue factor (TF) procoagulant activity was measured using plasma clotting assays.
- TF mRNA and antigen levels were quantified using RT-PCR and immunoassay, respectively.
- The effects of various K+ channel blockers (4-aminopyridine, tetraethylammonium chloride, apamin, charybdotoxin, glibenclamide) on TF expression were assessed.
Main Results:
- LPS stimulation significantly increased TF procoagulant activity, mRNA, and antigen levels in monocytes and THP-1 cells.
- K+ channel blockers 4-aminopyridine and tetraethylammonium chloride dose-dependently inhibited both basal and LPS-induced TF expression.
- Apamin, charybdotoxin, and glibenclamide showed differential or no inhibitory effects on TF expression, suggesting specific K+ channel involvement.
Conclusions:
- Cellular K+ channels, particularly those sensitive to 4-aminopyridine and tetraethylammonium chloride, play a crucial role in facilitating tissue factor (TF) synthesis in monocytes.
- Inhibition of specific K+ channels represents a potential therapeutic strategy to modulate TF-driven coagulation in inflammatory and thrombotic conditions.