Histamine upregulates the expression of inducible nitric oxide synthase in human intimal smooth muscle cells via histamine H1 receptor and NF-kappaB signaling pathway.
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.


RESULTS
In cultured human intimal SMCs, histamine increased NO production, iNOS expression, and NF-kappaB nuclear translocation, which were inhibited by histamine H1 blocker and NF-kappaB inhibitor. Luciferase assay using -8.3 kb upstream of human iNOS promoter region and electrophoretic mobility shift assay suggested that a NF-kappaB motif located at -3922 to -3914 would be necessary for histamine-inducible promoter activity. In addition, H1 blocker, NF-kappaB inhibitor, and dominant negative IkappaB alpha or IkappaB kinase beta 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-kappaB signaling pathway. Histamine could be one of NO-regulating factors, by inducing iNOS expression in intimal SMCs, and may be related to atherogenesis.
Tanimoto
Akihide
A
Department of Pathology and Cell Biology, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi, Kitakyushu 807-8555, Japan. aki@med.uoeh-u.ac.jp
Wang
Ke-Yong
KY
Murata
Yoshitaka
Y
Kimura
Satoshi
S
Nomaguchi
Masako
M
Nakata
Sei
S
Tsutsui
Masato
M
Sasaguri
Yasuyuki
Y
D000704:Analysis of Variance; D015152:Blotting, Northern; D015153:Blotting, Western; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006632:Histamine / Q000494:pharmacology*; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D011336:Probability; D011969:Receptors, Histamine H1 / Q000378:metabolism; D012680:Sensitivity and Specificity; D015398:Signal Transduction; D017539:Tunica Intima / Q000166:cytology / Q000378:metabolism; D015854:Up-Regulation
D016328:NF-kappa B; D011969:Receptors, Histamine H1; D006632:Histamine; D052247:Nitric Oxide Synthase Type II