Differential leukotriene receptor expression and calcium responses in endothelial cells and macrophages indicate 5-lipoxygenase-dependent circuits of inflammation and atherogenesis.
OBJECTIVE
Inflammatory infiltrates and atherosclerotic lesions emerge when monocytes adhere to endothelial cells (ECs), migrate into the subendothelial space, and become macrophages (MPhi(s)). Leukotrienes (LTs), products of 5-lipoxygenase, are powerful inflammatory mediators. 5-lipoxygenase+ MPhi(s) 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 MPhi(s).


RESULTS
HUVECs primarily expressed transcripts of the cysteinyl (cys) LT2-R, which was strongly upregulated by interleukin-4. By contrast, MPhi(s) 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 MPhi(s) preferentially responded to LTD4; HUVECs, but not MPhi(s), 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 MPhi(s) returned to baseline within seconds and were nonoscillatory.


CONCLUSIONS
Our data raise the possibility that MPhi-derived LTs differentially activate cysLT2-Rs via paracrine stimulation and cysLT1-Rs via autocrine and paracrine stimulation during inflammation and atherogenesis.
Lötzer
Katharina
K
Institute for Vascular Medicine, Friedrich-Schiller-University of Jena, Erfurt, Germany.
Spanbroek
Rainer
R
Hildner
Markus
M
Urbach
Anja
A
Heller
Regine
R
Bretschneider
Ellen
E
Galczenski
Helen
H
Evans
Jilly F
JF
Habenicht
Andreas J R
AJ
D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D001161:Arteriosclerosis / Q000209:etiology / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000503:physiopathology; D008264:Macrophages / Q000378:metabolism*; D018077:Receptors, Leukotriene / Q000235:genetics* / Q000378:metabolism*; D015854:Up-Regulation
D018077:Receptors, Leukotriene; D001094:Arachidonate 5-Lipoxygenase; D002118:Calcium