Histamine induces tissue factor expression: implications for acute coronary syndromes.
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.


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.
Steffel
Jan
J
Cardiovascular Research, Physiology Institute, University of Zurich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
Akhmedov
Alexander
A
Greutert
Helen
H
Lüscher
Thomas F
TF
Tanner
Felix C
FC
D000208:Acute Disease; D002478:Cells, Cultured; D003327:Coronary Disease / Q000188:drug therapy* / Q000209:etiology; D042783:Endothelial Cells / Q000378:metabolism*; D006632:Histamine / Q000494:pharmacology*; D006634:Histamine H1 Antagonists / Q000627:therapeutic use; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008074:Lipoproteins / Q000096:biosynthesis; D020935:MAP Kinase Signaling System / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D011969:Receptors, Histamine H1 / Q000502:physiology; D013925:Thromboplastin / Q000096:biosynthesis*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D020741:rho GTP-Binding Proteins / Q000502:physiology
D006634:Histamine H1 Antagonists; D008070:Lipopolysaccharides; D008074:Lipoproteins; D011969:Receptors, Histamine H1; D014409:Tumor Necrosis Factor-alpha; C051928:lipoprotein-associated coagulation inhibitor; D006632:Histamine; D013925:Thromboplastin; D020741:rho GTP-Binding Proteins