Differential Leukotriene Receptor Expression and Calcium Responses in Endothelial Cells and Macrophages Indicate 5-Lipoxygenase–Dependent Circuits of Inflammation and Atherogenesis

Abstract

Objective— Inflammatory infiltrates and atherosclerotic lesions emerge when monocytes adhere to endothelial cells (ECs), migrate into the subendothelial space, and become macrophages (MΦs). Leukotrienes (LTs), products of 5-lipoxygenase, are powerful inflammatory mediators. 5-lipoxygenase + MΦs have been shown to increase during atherogenesis, and LT receptor (LT-R) transcripts were identified in diseased arteries. To investigate LT-Rs in cells involved in inflammation and atherogenesis, we used the in vitro models of human umbilical vein ECs (HUVECs) and monocyte-derived MΦs. Methods and Results— HUVECs primarily expressed transcripts of the cysteinyl (cys) LT 2 -R, which was strongly upregulated by interleukin-4. By contrast, MΦs predominantly expressed transcripts of the cysLT 1 -R. Calcium responses toward LTs revealed differential cysLT-R utilization by both cell types: HUVECs responded to both cysLTs, whereas MΦs preferentially responded to LTD 4 ; HUVECs, but not MΦs, were resistant toward a cysLT 1 -R antagonist, montelukast; cysLTs generated regular calcium oscillations in HUVECs that lasted >60 minutes, resulting in >500 oscillations per cell. By contrast, calcium elevations in MΦs returned to baseline within seconds and were nonoscillatory. Conclusions— Our data raise the possibility that MΦ-derived LTs differentially activate cysLT 2 -Rs via paracrine stimulation and cysLT 1 -Rs via autocrine and paracrine stimulation during inflammation and atherogenesis.