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* Division of Allergy, Clinical Immunology, and Rheumatology, Department of Medicine, University of Kansas Medical Center, Kansas City, KS 66160; and
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232
Although histamine plays an essential role in inflammation, its influence on cyclooxygenases (COX) and prostanoid homeostasis is not well understood. In this study, we investigated the effects of histamine on the expression of COX-1 and COX-2 and determined their contribution to the production of PGE2, prostacyclin (PGI2), and thromboxane A2 in human coronary artery endothelial cells (HCAEC). Incubation of HCAEC monolayers with histamine resulted in marked increases in the expression of COX-2 and production of PGI2 and PGE2 with no significant change in the expression of COX-1. Histamine-induced increases in PGI2 and PGE2 production were due to increased expression and function of COX-2 because gene silencing by small interfering RNA or inhibition of the catalytic activity by a COX-2 inhibitor blocked prostanoid production. The effects of histamine on COX-2 expression and prostanoid production were mediated through H1 receptors. In addition to the direct effect, histamine was found to amplify LPS-stimulated COX-2 expression and PGE2 and PGI2 production. In contrast, histamine did not stimulate thromboxane A2 production in resting or LPS-activated HCAEC. Histamine-induced increases in the production of PGE2 and PGI2 were associated with increased expression of mRNA encoding PGE2 and PGI2 synthases. The physiological role of histamine on the regulation of COX-2 expression in the vasculature is indicated by the findings that the expression of COX-2 mRNA, but not COX-1 mRNA, was markedly reduced in the aortic tissues of histidine decarboxylase null mice. Thus, histamine plays an important role in the regulation of COX-2 expression and prostanoid homeostasis in vascular endothelium.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grant R01-HL070101 and Joseph and Elizabeth Carey Arthritis Fund from the Kansas University Endowment Association.
2 Address correspondence and reprint requests to Dr. Kottarappat N. Dileepan, Department of Medicine, MS 2026, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160. E-mail address: kdileepan{at}kumc.edu
3 Abbreviations used in this paper: COX, cyclooxygenase; EGM-2 MV, endothelial cell growth medium; EIA, enzyme immunoassay; H1R, histamine H1 receptor; H2R, histamine H2 receptor; HCAEC, human coronary artery endothelial cell; HDC, histidine decarboxylase; PGI2, prostacyclin; siRNA, small interfering RNA; TX, thromboxane.
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