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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:e32.)
© 2003 American Heart Association, Inc.

Vascular Biology

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

Katharina Lötzer^*; Rainer Spanbroek^*; Markus Hildner; Anja Urbach; Regine Heller; Ellen Bretschneider; Helen Galczenski; Jilly F. Evans; Andreas J.R. Habenicht

From the Institute for Vascular Medicine (K.L., R.S., M.H., A.U., R.H., E.B., A.U.R.H.), Friedrich-Schiller-University of Jena, Erfurt, Germany, and the Department of Pharmacology (H.G., J.F.E.), Merck & Co, Inc, West Point, Pa.

Correspondence to Andreas Habenicht, Institute for Vascular Medicine, Friedrich-Schiller-University of Jena, Nordhäuser Str 78, 99089 Erfurt, Germany. E-mail Habenicht{at}zmkh.ef.uni-jena.de

Objective— Inflammatory infiltrates and atherosclerotic lesions emerge when monocytes adhere to endothelial cells (ECs), migrate into the subendothelial space, and become macrophages (Ms). Leukotrienes (LTs), products of 5-lipoxygenase, are powerful inflammatory mediators. 5-lipoxygenase⁺ Ms 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 Ms.

Methods and Results— HUVECs primarily expressed transcripts of the cysteinyl (cys) LT₂-R, which was strongly upregulated by interleukin-4. By contrast, Ms predominantly expressed transcripts of the cysLT₁-R. Calcium responses toward LTs revealed differential cysLT-R utilization by both cell types: HUVECs responded to both cysLTs, whereas Ms preferentially responded to LTD₄; HUVECs, but not Ms, were resistant toward a cysLT₁-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 Ms returned to baseline within seconds and were nonoscillatory.

Conclusions— Our data raise the possibility that M-derived LTs differentially activate cysLT₂-Rs via paracrine stimulation and cysLT₁-Rs via autocrine and paracrine stimulation during inflammation and atherogenesis.

Key Words: leukotriene receptors • endothelial cells • macrophages • inflammation • atherogenesis

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