on May 3, 2007
Published online before print May 3, 2007, doi: 10.1161/ATVBAHA.106.139089
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Submitted on February 2, 2005
Accepted on April 17, 2007
Histamine Upregulates the Expression of Inducible Nitric Oxide Synthase in Human Intimal Smooth Muscle Cells via Histamine H1 Receptor and NF-
B Signaling Pathway
Akihide Tanimoto *;
From the Department of Pathology and Cell Biology (A.T., K.-Y.W., S.K., Y.S.), the Second Department of Internal Medicine (S.N.), and the Department of Pharmacology (M.T.), School of Medicine, University of Occupational and Environmental Health, Kitakyushu, and Kyurin Omtest Laboratory (Y.M., M.N.), Kyurin Corporation, Kitakyushu, Japan.
* To whom correspondence should be addressed. E-mail: aki{at}med.uoeh-u.ac.jp.
Objective--Histamine increases endothelial nitric oxide (NO) production as an endothelium-dependent vasodilator, which acts as a vasoconstrictor in atherosclerotic coronary arteries. To investigate the relation between histamine and NO production in intimal smooth muscle cells (SMCs), we studied the effect of histamine on inducible NO synthase (iNOS) expression in the SMCs.
Methods and Results--In cultured human intimal SMCs, histamine increased NO production, iNOS expression, and NF-
B nuclear translocation, which were inhibited by histamine H1 blocker and NF-B inhibitor. Luciferase assay using -8.3 kb upstream of human iNOS promoter region and electrophoretic mobility shift assay suggested that a NF-B motif located at -3922 to -3914 would be necessary for histamine-inducible promoter activity. In addition, H1 blocker, NF-B inhibitor, and dominant negative IB
or IB kinase 
downregulated the histamine-induced iNOS promoter activity. In the human aorta, histamine content was estimated to be 310±66 pmol/mg protein in the atherosclerotic intima, while that was to be 43±22 pmol/mg protein in the media (P<0.001).
Conclusions--Histamine stimulates intimal SMCs to increase iNOS expression via H1 receptors and NF-B signaling pathway. Histamine could be one of NO-regulating factors, by inducing iNOS expression in intimal SMCs, and may be related to atherogenesis.
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