Histamine Induces Tissue Factor Expression

Abstract

Background— Histamine can induce coronary vasospasm, leading to variant angina and acute myocardial infarction. However, the role of histamine in thrombus formation is ill defined. Hence, this study investigates whether histamine induces tissue factor (TF) expression in vascular cells. Methods and Results— Histamine (10 ⁻⁸ to 10 ⁻⁵ mol/L) induced TF expression in a concentration-dependent manner in human aortic endothelial and vascular smooth muscle cells, whereas TF pathway inhibitor expression remained unaffected. RT-PCR and Northern blotting revealed that histamine stimulated TF mRNA transcription, peaking at 1 hour. Protein expression increased 18-fold ( P P 1 receptor antagonists mepyramine ( P 2 receptor antagonist cimetidine ( P =NS). Histamine induced a time-dependent, H ₁ receptor–mediated activation of p38 MAP kinase (p38), p44/42 MAP kinase (ERK), and c-jun terminal NH ₂ kinase (JNK). Blocking of p38, ERK, or JNK with SB203580 ( P P P Conclusions— Histamine induces expression of TF, but not TF pathway inhibitor, in vascular cells via activation of the H ₁ , but not H ₂ , receptor. This effect is mediated by the MAP kinases p38, ERK, and JNK. This observation may open novel perspectives in the treatment of variant angina and acute coronary syndromes.