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

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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.

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