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(Circulation. 2005;112:341-349.)
© 2005 American Heart Association, Inc.

Coronary Heart Disease

Histamine Induces Tissue Factor Expression

Implications for Acute Coronary Syndromes

Jan Steffel, MD; Alexander Akhmedov, PhD; Helen Greutert; Thomas F. Lüscher, MD; Felix C. Tanner, MD

From Cardiovascular Research, Physiology Institute, University of Zürich (J.S., A.A., H.G., T.F.L., F.C.T.), Center for Integrative Human Physiology, University of Zürich (J.S., A.A., H.G., T.F.L., F.C.T.), and Cardiology, Cardiovascular Center, University Hospital Zürich (J.S., T.F.L., F.C.T.), Zürich, Switzerland.

Correspondence to Felix C. Tanner, MD, Cardiovascular Research, Physiology Institute, University of Zurich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland. E-mail felix.tanner{at}access.unizh.ch

Received August 20, 2004; revision received November 28, 2004; second revision received April 5, 2005; accepted April 11, 2005.

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<0.02) with a maximum at 5 hours, which was paralleled by a 4-fold augmentation in surface activity (P<0.01). These effects were completely prevented by pretreatment with the H₁ receptor antagonists mepyramine (P<0.0001), chlorpheniramine, and diphenhydramine but not the H₂ receptor antagonist cimetidine (P=NS). Histamine induced a time-dependent, H₁ receptor–mediated activation of p38 MAP kinase (p38), p44/42 MAP kinase (ERK), and c-jun terminal NH₂ kinase (JNK). Blocking of p38, ERK, or JNK with SB203580 (P<0.0001), PD98059 (P<0.0001), or SP600125 (P<0.0001), respectively, impaired histamine-induced TF expression in a concentration-dependent manner. In contrast, histamine-stimulated TF expression was increased by phosphatidylinositol 3-kinase inhibition with LY294002 or wortmannin, whereas it was not affected by Rho-kinase inhibition with Y-27632 or hydroxyfasudil.

Conclusions— Histamine induces expression of TF, but not TF pathway inhibitor, in vascular cells via activation of the H₁, but not H₂, 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.

Key Words: coagulation • coronary disease • endothelium • signal transduction • thrombosis

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