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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

	Abstract

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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

	Introduction

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Leukotriene B₄ (LTB₄) and the cysteinyl (cys) LTs, LTC₄, LTD₄, and LTE₄, are potent, proinflammatory mediators.^1,2 Four LT-activated, putative, 7 transmembrane G protein–coupled receptors have been characterized: 2 receptors for LTB₄, namely BLT-Rs,^3,4 and 2 receptors for LTD₄ and LTC₄, namely, cysLT-Rs.^5,6 Whereas LTB₄ mediates chemotaxis,³ cysLTs trigger a variety of tissue responses, including increases in vascular permeability.⁷ CysLT₁-R is primarily present in the spleen, blood leukocytes, and lung macrophages (Ms),⁵ whereas cysLT₂-R is expressed in the heart and brain.⁶ However, the precise cell lineage–specific expression of LT-Rs, their mode of regulation, and the signaling pathways that they trigger remain to be determined.

We observed transcripts of all 4 LT-Rs in human atherosclerotic lesions.⁸ These data raised the possibility that the 5-lipoxygenase (5-LO) pathway forms foci of inflammation within the arterial wall. Because human umbilical vein endothelial cells (HUVECs) and Ms have been used to study inflammation and recent studies have associated the 5-LO pathway with experimental atherosclerosis,^9–15 we examined their LT-R expression patterns and characterized their calcium responses.

	Methods

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Montelukast (Singulair) was a kind gift of Dr R.N. Young, Merck Frosst (Quebec, Canada). BAY u9773 was obtained from Biomol; fura 2-AM, from Calbiochem; fluo 4-AM, from Molecular Probes; transforming growth factor-ß1 (TGF ß-1), interleukin-1ß (IL-1ß), tumor necrosis factor- (TNF-), and IL-4, from R&D Systems; LTs, from Cayman Chemicals; CD14 MicroBeads, from Miltenyi Biotech; and other reagents, from Sigma. Monocytes were purified from peripheral blood mononuclear cells by adherence or CD14 microbead adsorption and maintained at 1x10⁶ cells/mL for 5 to 9 days in RPMI-1640 medium plus 20% autologous human serum. HUVECs were cultured as described¹⁶ and used at passages 1 to 2. Carotid artery disease lesions were obtained after informed consent of the patients, as described.⁸ HUVECs or Ms were loaded with fura 2-AM at 4 µmol/L, and changes in calcium ions were expressed as excitation ratios of 340 nm/380 nm at 510 nm. For single-cell measurements, cells were loaded with 2 µmol/L fluo 4-AM. Responses were recorded on a microscope (Axiovert 200M) equipped with a confocal laser scanning head (LSM510). Quantitative (real-time) reverse transcription–polymerase chain reaction (qRT-PCR) was performed as previously reported.⁸

	Results

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Expression Patterns of LT-R Transcripts in HUVECs and Ms
Determination of sequence-confirmed RT-PCR products of LT-Rs in HUVECs and Ms indicated differential expression of transcript levels. Preliminary, nonquantitative RT-PCR analyses indicated that HUVECs showed significant cysLT₂-R and detectable BLT₁-R and BLT₂-R but no or low cysLT₁-R transcripts. By contrast, Ms preferentially expressed cysLT₁-R transcripts and, to a lesser extent, cysLT₂-R, BLT₁-R, and BLT₂-R transcripts (Figure 1a). qRT-PCR demonstrated the magnitude of differential LT-R transcript expression in both cell types (when expressed as absolute transcripts/10⁵ glyceraldehyde 3-phosphate dehydrogenase [GAPDH] transcripts): HUVECs expressed cysLT₂-Rs in large excess when compared with cysLT₁-Rs (cysLT₂-Rs, 983±527; cysLT₁-R, 3±3; n=6). By contrast, Ms expressed cysLT₁-Rs in large excess when compared with cysLT₂-Rs (cysLT₁-Rs, 6754±4507; cysLT₂-R, 156±123; n=8). Interestingly, carotid artery disease lesions that represent advanced atherosclerotic lesions (type V) according to the American Heart Association nomenclature⁸ expressed cysLT₁-Rs that were only 3-fold higher than cysLT₂-Rs (cysLT₁-R, 439±158; cysLT₂-R, 129±53; n=5). The numbers represent mean±SD and are highly significant: P<0.01 for cysLT₁R versus cysLT₂R in HUVECs and Ms. These data show that HUVECs expressed cysLT₂-R transcripts at >2 orders of magnitude higher levels when compared with cysLT₁-R transcripts.

View larger version (27K): [in this window] [in a new window]   Figure 1. Differential LT-R expression in HUVECs and Ms. HUVECs and Ms were examined for LT-R transcript expression by RT-PCR (a) or qRT-PCR (b–d) as described in Methods. HUVECs were seeded at 1 to 2x104 cells/cm2 and maintained for 3 days until they reached subconfluence. Cells were stimulated with IL-4 at 50 ng/mL; TGF-ß1 at 5 ng/mL; IL-1ß at 100 U/mL, and TNF- at 100 U/mL for 24 hours (b); increasing concentrations of IL-4 for 48 hours (c); or 10 ng/mL IL-4 for increasing periods of time (d). Control cells (open columns) received carrier for 24 hours (b) or 48 hours (c). IL-4–stimulated cells were different from controls at P<0.05 (b), P<0.02 (at 1 nmol/L IL-4; c), P<0.001 (at 10 nmol/L IL-4; c) or P<0.02 (48 hours; d) (all by Student’s t test). TNF- treatment significantly reduced transcript numbers of cysLT2-R (P<0.04; n=3). Experiments were performed at least twice, and values were normalized to nanograms of RNA; there was no change of GAPDH transcripts per nanogram RNA on cytokine treatment.

Cytokines implicated in inflammation and atherogenesis were examined for regulation of cysLT₂-R transcripts. IL-4, but not IL-1ß, TGF-ß1, or TNF- (Figure 1b), caused upregulation of cysLT₂-R transcripts in a concentration- and time-dependent way (Figure 1c and 1d). Confluent HUVECs expressed 2-fold higher numbers of cysLT₂-R transcripts when compared with their rapidly proliferating counterparts (Figure 1d, open columns). Because both IL-4 and cell density contributed to cysLT₂-R transcript upregulation in an additive way, this amounted to a 7-fold increase at 48 and 72 hours. Moreover, levels of cysLT₂-R transcript decreased with increasing passage numbers.

Calcium Responses Indicate Differential cysLT-R Utilization by HUVECs and Ms
In receptor-transfected cells, cysLT₁-R has been shown to bind LTC₄ with lower affinity than LTD₄, whereas the cysLT₂-R binds LTC₄ and LTD₄ with similar affinities, but functional studies of cysLT₁-R versus cysLT₂-R in HUVECs have not yet been reported.^5,6 Initially, calcium responses toward LTC₄/LTD₄ of HUVECs and Ms were examined. LTC₄ or LTD₄ (50 nmol/L) triggered robust calcium rises with similar potencies in HUVECs, whereas the selective cysLT₁-R antagonist montelukast (Singulair) failed to inhibit calcium transients (Figure 2a and 2b). Moreover, BAY u9773, a partial cysLT₂-R agonist,¹⁷ induced a moderate response (Figure 2b). By contrast, 50 nmol/L LTD₄ triggered robust calcium responses in Ms, whereas LTC₄ at 50 nmol/L was inactive, and LTD₄-dependent calcium responses were completely blocked by montelukast (Singulair; Figure 2c). These data are consistent with and extend studies reported by others that cysLTs cause calcium elevations in cultured HUVECs and Ms.^18–20 Thus, our data demonstrate for the first time that the dominant, functional cysLT-R in HUVECs is the cysLT₂-R. They establish HUVECs as a culture system in which selective activation of the cysLT₂-R for the biology of ECs can be studied.

View larger version (45K): [in this window] [in a new window]   Figure 2. Pharmacologic profiles of cysLT-dependent calcium transients in HUVECs and Ms and determination of calcium in single cells. Cells loaded with fura-2 were stimulated with agonists, montelukast (Singulair), or ethanol as indicated, and calcium transients were determined as described in Methods (a–c). Changes in fura-2 fluorescence (a–c) are expressed as fluorescence ratios and normalized to the scale indicated in a. Cells were loaded with fluo-4: an HUVEC (d) or an M (e) was examined during the initial Ca2+ response. An HUVEC was examined during 2 oscillations after the initial rise of calcium ions in response to 1 µmol/L LTC4 had occurred and scanned at 1.79-second intervals (f); an M was examined after addition of 500 nmol/L LTD4 (g) and scanned at 1.58-second intervals. 2.5D (upper row in f) and 2D (lower row in f) scans reveal an HUVEC cytosolic calcium puff close to the nucleus (arrow) that spreads into a calcium wave to encompass the nucleus within <2 seconds. Data are representative of at least 3 independent experiments.

Calcium Elevations in HUVECs and Ms Reveal Differences in Kinetics, Amplitude, Duration, and Oscillatory Patterns
We noted that the initial rise of calcium ions in HUVECs was followed by a pronounced, sustained component, whereas that in Ms rapidly returned to near-baseline levels within seconds (compare Figure 2a, 2b, and 2c). We next determined calcium responses in single cells. In HUVECs, the rapid initial LTC₄/D₄-dependent rise in calcium ions was followed by oscillations that, once established, proceeded at regular intervals (Figure 2d). These data confirmed studies by Datta et al,¹⁸ who demonstrated that cysLTs trigger oscillatory calcium rises in HUVECs. By contrast, in Ms, LTD₄ induced an initial increase in calcium ions, which rapidly returned to baseline levels (Figure 2e) and was only rarely followed by single or irregular oscillations. These data show that oscillations are not invariably associated with the action of LTs on target cells, although they appear to depend on both the LT-R subtype and/or the target cell. We next initiated more detailed studies of the pharmacology, LT-R dependence, regularity, duration, intracellular location, variability, and dependence on culture conditions of oscillations in HUVECs. The frequency of oscillations did not vary considerably in individual HUVECs for extended periods of time, although variability was noted between individual HUVECs. LT-dependent oscillations in HUVECs originated in subcellular areas in the cytoplasm (Figure 2f, arrow). Increases in calcium occurred in both the cytosol and the nucleus, whereby the nucleus was affected secondary to cytoplasmic calcium waves (Figure 2f). Once generated in one EC, cysLT-triggered calcium waves appeared to be transferred to other ECs, thus generating global intercellular calcium waves, probably through gap junctions. This interpretation was supported by inspection of slow-motion recordings of oscillations across intact portions of the monolayer that revealed areas of ECs in which coordinated calcium oscillations that originated in calcium "puffs" of a single EC were observed. Importantly, calcium oscillations were a response to cysLT₂-R activation, because montelukast failed to eliminate them (not shown). Moreover, calcium oscillations were dependent on extracellular calcium, because EGTA did not prevent the initial rise in calcium ions but led to an immediate cessation of ongoing oscillations. Culture parameters also influenced characteristics of calcium oscillations: a higher percentage of early-passage HUVECs responded to low concentrations of cysLTs when compared with higher-passage HUVECs, and this response was correlated with cysLT₂-R transcripts; the frequency of oscillations was correlated with the concentration of the agonist. At 1 µmol/L LTC₄, the oscillation periods of HUVECs persisted for >60 minutes, resulting in >500 oscillations/h per HUVEC, whereas the response to another G protein–coupled receptor agonist, thrombin, was short-lived and subsided within seconds.

	Discussion

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HUVECs principally expressed cysLT₂-Rs, which were upregulated 7-fold by a combination of IL-4 and cell density (Figure 1). By contrast, HUVECs did not express significant numbers of cysLT₁-Rs (Figures 1a, 2a, and 2b), yet Ms principally expressed cysLT₁-Rs (Figures 1a and 2c). Because selective cysLT₂-R antagonists are not yet available, these data establish HUVECs as the first bona fide cell system in which the signaling pathway of the cysLT₂-R can be studied without interfering with cysLT₁-R–dependent signaling. The cysLT-R expression patterns in HUVECs and Ms yielded calcium transients with very different properties: HUVECs and Ms differed in their sensitivities toward LTC₄ and LTD₄ (Figure 2); response to LT-R antagonists; kinetics, regularity, and duration of calcium increases; and oscillatory versus nonoscillatory patterns.

When previous and the present data on expression of the 5-LO pathway and LT-Rs in ECs, Ms, and advanced human atherosclerotic lesions are considered, our data raise the possibility that leukocyte/EC/T-cell interactions might constitute inflammatory "circuits" through at least 2 major mechanisms: M-derived LTs might activate cysLT₁-Rs via autocrine mechanisms and EC cysLT₂-Rs and T-lymphocyte cysLT₁-Rs, via paracrine mechanisms during physiologic leukocyte trafficking, inflammation, and atherogenesis (Figure 3).

View larger version (60K): [in this window] [in a new window]   Figure 3. Hypothetical actions of M-derived LTs acting on cells at sites of inflammation and atherosclerosis. Ms/foam cells/dendritic cells/mast cells produce LTs in response to unknown agonists. cysLTs activate cysLT2-Rs expressed on ECs and additional neighboring cells, such as T lymphocytes or smooth muscle cells, in a paracrine manner and cysLT1-Rs on Ms/MFCs in an autocrine and/or paracrine way. For clarity, transcellular LT formation has not been depicted. cPLA2 indicates cytosolic phospholipase A2; FLAP, 5-LO–activating protein; LTA4H, leukotriene A4 hydrolase; LTC4S, leukotriene C4 synthase; AA, arachidonic acid); and 5-H(P)ETE, 5-hydr(oper)oxyeicosatetraenoic acid.

	Acknowledgments

 
This study was supported by grants of the Deutsche Forschungsgemeinschaft (Ha 1083/13–1/13–2), the European Union research network (QLG1-CT-2001–01521), and the Interdisziplinäre Zentrum für Klinische Forschung, Jena. We thank C. Ströhl, M. Franke, and E. Teuscher for expert technical assistance.

	Footnotes

 
*These authors contributed equally to this work.

Received May 21, 2003; accepted June 4, 2003.

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This Article Abstract Full Text (PDF) All Versions of this Article: 23/8/e32    most recent 01.ATV.0000082690.23131.CBv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lötzer, K. Articles by Habenicht, A. J.R. Search for Related Content PubMed PubMed Citation Articles by Lötzer, K. Articles by Habenicht, A. J.R. Related Collections Coagulation Coagulation and fibronolysis Catheter-based coronary and valvular interventions: other CV surgery: other