Histamine Directly and Synergistically with Lipopolysaccharide Stimulates Cyclooxygenase-2 Expression and Prostaglandin I2 and E2 Production in Human Coronary Artery Endothelial Cells

Abstract

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.

Histamine Induces Egr-1 Expression in Human Aortic Endothelial Cells via the H1 Receptor-mediated Protein Kinase Cδ-dependent ERK Activation Pathway

“…Related to our finding, previous studies have shown that histamine-induced expression of p-selectin (9), ICAM1, VCAM1 (10), IL6, IL8 (8), cyclooxygenase-2 (27), and tissue factor (11) is mediated by the H1 receptor in vascular endothelial cells. Taken together, our results and the previous observations support a notion that histamine-induced expression of the pro-inflammatory transcription factor Egr-1 and its downstream inflammatory genes is selectively mediated by the H1 receptor in endothelial cells.…”

“…One of these studies showed that the histamine H1 receptor antagonist reduced intimal hyperplasia (13); the other study reported that histamine synthesis enzyme knock-out mice (HDC Ϫ/Ϫ mice) showed reduced neointimal thickening and a decreased intima-to-media thickness ratio (14). In regard to how histamine influences inflammation and atherosclerosis in endothelial cells, evidence has shown that histamine induces expression of genes such as p-selectin (9), ICAM1, VCAM1 (10), IL6, IL8 (8), cyclooxygenase-2 (27), and tissue factor (11). The products of these genes have been shown to promote inflammation and atherogenesis (28,29).…”

“…Our data also imply that CREB, a downstream component of the ERK pathway, regulates Egr-1 expression in HAECs. Because it was reported previously that histamine induces the expression of p-selectin (9), ICAM1, VCAM1 (10), IL6, IL8 (8), cyclooxygenase-2 (27), and tissue factor (11) in endothelial cells, and that Egr-1 can serve as a transcription factor for regulating these genes in response to other stimuli (15, 30 -32), our result that histamine induces Egr-1 expression points out that Egr-1 may be the previously missed link between histamine and the pro-inflammatory genes. Of particular significance is that our findings imply that histamine-induced Egr-1 transcription activity could serve as a central control regulating transduction of the histamine signal and consequently governing histamine induction of multiple inflammatory genes, which in turn, trigger inflammation and atherosclerosis.…”

Activation of the PGI 2 /IP System Contributes to the Development of Circulatory Failure in a Rat Model of Endotoxic Shock

“…18,19 However, during inflammation, endothelial cells are capable of producing PGI 2 in a COX-2-dependent manner. 20 Notably, during severe sepsis, it has been suggested that high levels of endotoxin result in a complete loss of the endothelium and of course also of its function. 21 In this context, it has been shown that VSMCs are also able to produce PGI 2 in a COX-2-dependent manner in response to LPS.…”

Acyl chain-dependent effect of lysophosphatidylcholine on endothelial prostacyclin production

“…Considering the fact that HAEC, like human coronary artery endothelial cells (HCAEC) ( 44 ), express PGI 2 synthase (PGIS), PGE 2 synthase (mPGES-1), and thromboxane synthase (TBXS) (not shown), it is conceivable that those prostanoids are products of enzymatic transformation of PGH 2 . However, we cannot completely exclude the possibility that a portion of the secreted prostanoids is generated by spontaneous, nonenzymatic transformation of PGH 2 ( 45 ).…”