This Article Abstract Full Text (PDF) All Versions of this Article: 23/8/e37    most recent 01.ATV.0000082689.46538.DFv1 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 Sjöström, M. Articles by Haeggström, J. Z. Search for Related Content PubMed PubMed Citation Articles by Sjöström, M. Articles by Haeggström, J. Z. Related Collections Health policy and outcome research Other Ethics and Policy Coagulation inhibitors Endothelium/vascular type/nitric oxide

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:e37.)
© 2003 American Heart Association, Inc.

Vascular Biology

Dominant Expression of the CysLT₂ Receptor Accounts for Calcium Signaling by Cysteinyl Leukotrienes in Human Umbilical Vein Endothelial Cells

Mattias Sjöström^*; Anne-Sofie Johansson^*; Oliver Schröder; Hong Qiu; Jan Palmblad; Jesper Z. Haeggström

From the Department of Medical Biochemistry and Biophysics (M.S., O.S., H.Q., J.Z.H.), Division of Chemistry 2, Karolinska Institutet, and the Center for Inflammation and Hematology Research (A.-S.J., J.P.), Department of Medicine, Huddinge University Hospital, Karolinska Institutet, Stockholm, Sweden.

Correspondence to Jesper Z. Haeggström, MD, PhD, Department of Medical Biochemistry and Biophysics, Division of Chemistry 2, Karolinska Institutet, S-171 77 Stockholm, Sweden. E-mail jesper.haeggstrom{at}mbb.ki.se

	Abstract

Top Abstract Introduction Methods Results and Discussion References

 
Objective— The objective of the present study was to identify and characterize the cell-surface receptors on human umbilical vein endothelial cells (HUVECs) that transduce calcium transients elicited by cysteinyl leukotrienes (CysLTs), potent spasmogenic and proinflammatory agents with profound effects on the cardiovascular system.

Methods and Results— Using quantitative reverse transcription–polymerase chain reaction, we found that HUVECs abundantly express CysLT₂R mRNA in vast excess (>4000-fold) of CysLT₁R mRNA. Lipopolysaccharide, tumor necrosis factor-, or interleukin-1ß caused a rapid (within 30 minutes) and partially reversible suppression of CysLT₂R mRNA levels. Challenge of HUVECs with BAY u9773, a specific CysLT₂R agonist, triggered diagnostic Ca²⁺ transients. LTC₄ and LTD₄ are equipotent agonists, and their actions can be blocked by the dual-receptor antagonist BAY u9773, but not by the CysLT₁R-selective antagonist MK571.

Conclusions— HUVECs almost exclusively express the CysLT₂R. Furthermore, Ca²⁺ fluxes elicited by CysLT in these cells emanate from perturbation of the CysLT₂R, rather than the expected CysLT₁R. Hence, signaling events involving CysLT₂R might trigger functional responses involved in the critical components of LT-dependant vascular reactions, which in turn have implications for ischemic heart disease and myocardial infarction.

Key Words: leukotrienes • endothelial cells • receptors • inflammation • arteriosclerosis

	Introduction

Top Abstract Introduction Methods Results and Discussion References

 
The cysteinyl leukotrienes (CysLTs) are a family of powerful lipid mediators, typically formed by eosinophils, basophils, monocytes, and mast cells, which are involved in critical steps of inflammatory and allergic diseases, particularly in the respiratory tract and cardiovascular system.¹ The CysLTs are biosynthesized from arachidonic acid and its oxygenation product, LTA₄ [5(S)-trans-5,6-oxido-7,9-trans-11,14-cis-eicosatetraenoic acid], generated by the enzyme 5-lipoxygenase. LTA₄ is further conjugated with reduced glutathione by LTC₄ synthase to form LTC₄ [5(S)-hydroxy-6(R)-S-glutathionyl-7,9-trans-11,14-cis-eicosatetraenoic acid), ie, the parent compound of the CysLTs (LTC₄, LTD₄, and LTE₄). The biologic effects of CysLTs are signaled through 2 principal G protein–coupled receptors, designated CysLT₁R and CysLT₂R.^2,3 The biologic role of the CysLT₂R is presently not known, but its mRNA expression profile suggests that it might have important functions in the cardiovascular system.^3–6

Endothelial cells are strategically located at the interphase between the blood and parenchymal cells, where they take active part in physiologic and pathologic processes involving the vessel wall. Under inflammatory conditions, these cells are directly exposed to LTs that are formed by activated, adhering leukocytes or via transcellular routes involving platelets or endothelial cells themselves.^7–9 The CysLTs in turn trigger a number of specific functional responses in endothelial cells, eg, synthesis of platelet-activating factor (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine), secretion of von Willebrand factor, and expression of P-selectin, all of which might contribute to vascular inflammation.^10,11 Here we report that human umbilical vein endothelial cells (HUVECs) abundantly express the CysLT₂R in vast excess over the CysLT₁R. Moreover, CysLT₂R transduces Ca²⁺ signals elicited by CysLTs in these cells, which in turn might be linked to pathologic processes of the vessel wall.

	Methods

Top Abstract Introduction Methods Results and Discussion References

 
Materials
LTC₄ and LTD₄ were from BioMol, whereas MK571 and BAY u9773 were kind gifts from Dr Sven-Erik Dahlén, Karolinska Institutet, Stockholm, Sweden. Oligonucleotides were from Cybergene AB. Lipopolysaccharide (LPS) from Escherichia coli serotype O55:B5, tumor necrosis factor- (TNF-), interleukin (IL)-1ß, and fura 2-AM were from Sigma Chemical Co.

Cell Culturing
HUVECs were obtained from vessels by collagenase treatment and were then cultivated and identified, as described.^12,13 The cell viability was >95%, as judged by cell morphology, trypan blue exclusion, and analysis of lactate dehydrogenase release. Glass dishes were seeded with 10⁴ HUVECs per well and grown to confluence.

Analysis of mRNA by RT-PCR and Real-Time RT-PCR
Preparation of total RNA and reverse transcription–polymerase chain reaction (RT-PCR) were performed essentially as described.¹⁴ In nested PCR analyses, 12 +20 cycles (CysLT₂R mRNA) or 40 +40 cycles (CysLT₁R mRNA) were used for the first set (5'-ATGGAG-AGAAAATTTATGTCC; 5'-AATAGAGCAGAGGATTGAAGC) and second set (5'-ACCTTCAGCAATAACAACAGC; 5'-CTTTA- TGCAGTCTGTCTTTGC) of primers, respectively (Figure 1). One of 2 housekeeping genes (glyceraldehyde 3-phosphate dehydrogenase and ß-actin) was amplified as an internal standard and tested for potential responsiveness to the cell stimulus before calculations. For semiquantitative analysis of PCR products, a fluorescent dye (PicoGreen, Molecular Probes) was used according to the manufacturer’s instructions.¹⁵ The fluorescence was measured (excitation wavelength=485 nm; emission wavelength=538 nm) in a fluorometer (SpectraMax GeminiXS). For comparative RT-PCR, total RNA was diluted until the PCR signal for CysLT₂R was comparable to that of CysLT₁R in undiluted RNA, with the use of 40 +40 cycles. To correct for differences in template efficiency, equal amounts of CysLT₁R and CysLT₂R DNA standards were subjected to PCR amplification, and the relative signal intensity was used for normalization. Real-time RT-PCR was performed on a commercially available amplification system (Rotor Gene 2000, Corbett Research Mortlake) with SYBRgreen (Roche Diagnostics) as the detection dye.¹⁶

View larger version (26K): [in this window] [in a new window]   Figure 1. Dominant expression of CysLT2R mRNA in HUVECs. A, RT-PCR analysis of CysLT1R (947 bp) and CysLT2R mRNA (793 bp). Samples were amplified with 12 +20 PCR cycles for analysis of CysLT1R (lane 2) and CysLT2R (lane 3) mRNA or 40 +40 cycles for identification of CysLT1R mRNA (lane 4). PCR products were analyzed by agarose gel electrophoresis. B, Comparative RT-PCR of CysLT2R (blue bar) and CysLT1R (red bar) mRNA (mean±SD, n=6, ***P<0.001), as described in Methods. C, Real-time RT-PCR quantification of CysLT2R (blue traces) and CysLT1R (red traces) mRNA (typical experiment of n=9). Standards were as follows: 1=25 000, 2=5000, 3=1000, 4=200, and 5=40 molecules.

Ca²⁺ Mobilization Experiments
Mobilization of cytosolic calcium, Ca²⁺_i, was monitored spectrophotometrically with the use of fura 2-AM, essentially as described.¹³ The results are given as the ratio of fluorescence between 340 and 380 nm, calibrated and calculated with commercially available software (Miracal, Life Science Resources Ltd), according to the recommendations of the manufacturer.

	Results and Discussion

Top Abstract Introduction Methods Results and Discussion References

 
Dominant Expression of CysLT₂R mRNA in HUVECs
Nested RT-PCR analyses (12 +20 cycles) of total RNA from HUVECs generated a robust signal, corresponding to CysLT₂R mRNA (793 bp), whereas no signal for CysLT₁R could be detected (Figure 1). However, when the number of cycles was increased to 40 +40, a weak signal for CysLT₁R mRNA (947 bp) was obtained, as previously reported.¹⁴ To quantify the difference in mRNA levels, we made serial dilutions of the total RNA until the signal for CysLT₂R was comparable to that of CysLT₁R in undiluted RNA and then corrected the signal intensities for differences in template efficiency (Figure 1). With this technique, the ratio of CysLT₂R mRNA to CysLT₁R mRNA was calculated as >4000:1. In addition, real-time RT-PCR detected 2130 molecules of CysLT₂R mRNA and 4 molecules of CysLT₁R mRNA, indicating a 500-fold difference in mRNA levels (Figure 1). However, cautious interpretation is warranted, because the value for CysLT₂R transcripts was obtained by extrapolation outside the linear portion of the standard curve.

Rapid Suppression of CysLT₂R mRNA Levels by LPS, IL-1ß, and TNF-
Treatment of HUVECs with LPS (100 ng/mL), IL-1ß (5 U/mL), or TNF- (10 ng/mL) for 30, 60, and 120 minutes led to rapid (30 to 60 minutes) suppression (30% to 60%) of the CysLT₂R mRNA level (Figure 2). The effects of LPS were reversible, whereas those of IL-1ß and TNF- persisted after 120 minutes, with mRNA levels 20% and 40%, respectively, below those of controls, suggesting that these cytokines reduce the expression of CysLT₂R. The levels of CysLT₁R mRNA remained very low, and no significant alterations could be detected (data not shown).

View larger version (18K): [in this window] [in a new window]   Figure 2. Effects of LPS, IL-1ß, and TNF- on CysLT2R mRNA levels in HUVECs. HUVECs were treated with different cytokines for 0, 30, 60, and 120 minutes. Aliquots of total RNA, prepared from cells harvested after different treatments and time points, were subjected to RT-PCR for analysis of CysLT2R mRNA. The figure depicts time-dependent effects on CysLT2R mRNA by treatment with LPS (), IL-1ß (•), and TNF- (). Statistical significance of differences in mRNA levels were evaluated with Student’s t test and are expressed as mean±SD, n=3 to 8: **0.01>P>0.001, ***P<0.001.

Challenge of HUVECs With LTC₄, LTD₄, and BAY u9773 Elicits Ca²⁺ Transients That Are Diagnostic for CysLT₂R
In the absence of reliable antibodies against CysLT₂R, we used the natural agonists LTC₄ and LTD₄, together with the specific CysLT₂R agonist BAY u9773, to identify and functionally characterize CysLT₂R on HUVECs. Thus, stimulation of HUVECs with either LTC₄ or LTD₄ (100 nmol/L) elicited a Ca²⁺ response that peaked after 5 to 10 seconds and lasted for nearly 1 minute (Figure 3). The 2 ligands were almost equipotent, in agreement with the typical ligand specificity of the CysLT₂R (LTC₄LTD₄)^3–5 and exhibited kinetics, which closely resembled that of thrombin and other G protein–coupled surface receptors on HUVECs.¹³ Furthermore, stimulation of HUVECs with BAY u9773⁴ elicited a significant Ca²⁺ response of almost the same strength as that of LTC₄ and LTD₄, thus providing direct evidence for the presence of functionally intact CysLT₂R (Figure 3). Moreover, an initial challenge with LTD₄ blocked the Ca²⁺ response to subsequent (1-minute) stimulation with BAY u9773 (Figure 3), indicating CysLT₂R occupancy or desensitization.

View larger version (14K): [in this window] [in a new window]   Figure 3. Intracellular mobilization of Ca2+ in HUVECs by LTC4, LTD4, and BAY u9773, desensitization by LTD4, and differential effects of receptor antagonists. A, Intracellular mobilization of Ca2+ in HUVECs challenged (arrow) with LTC4 (100 nmol/L), LTD4 (100 nmol/L), or thrombin (0.1 U/mL). B, Mobilization of Ca2+ by 100 nmol/L BAY u9773 (upper trace) and desensitization of this response by pretreatment with 100 nmol/L LTD4 (lower trace). C, Treatment of HUVECs with BAY u9773 (1 µmol/L) for 15 minutes inhibits ligand-induced Ca2+ mobilization in HUVECs (top), whereas MK571 fails to inhibit the action of either LTC4 or LTD4 (bottom).

CysLT₂R Is the Major Functional Receptor for CysLTs in HUVECs
At present, there is no selective CysLT₂R antagonist available. However, BAY u9773 is not only a CysLT₂R agonist (see Methods) but also a dual CysLT₁R and CysLT₂R antagonist.⁴ Therefore, we used BAY u9773 together with MK571, a selective CysLT₁R antagonist, to assess the role of CysLT₂R in CysLT-induced Ca²⁺ signaling. Preincubation of HUVECs for 15 minutes with 1 µmol/L BAY u9773 completely blocked the Ca²⁺ responses to a subsequent stimulation with 100 nmol/L of either LTC₄ or LTD₄ (Figure 3). In contrast, MK571 (1 µmol/L, 15 minutes) was a very poor antagonist and could only partially, if at all, prevent subsequent Ca²⁺ mobilization by 100 nmol/L LTC₄ or LTD₄ (Figure 3). This pharmacologic profile, together with the similar agonistic potency of LTC₄ and LTD₄, as well as the high level of mRNA (cf Figure 1), strongly indicates that HUVECs almost exclusively express the CysLT₂R and that this receptor accounts for the Ca²⁺ signals induced by CysLTs in these cells. It should be noted that we and others have previously reported that HUVECs express the CysLT₁R, albeit at a low level, unless the cells are subjected to long-term treatment with IL-1ß.^14,17 In light of the results of the present study, it seems likely that CysLT₁R on HUVECs lacks functional integrity and will not contribute significantly to Ca²⁺ signaling triggered by CysLTs.

Potential Role of CysLT₂R in the Cardiovascular System
CysLTs have profound effects in the vascular system and constrict coronary vessels with a negative inotropic effect and reduced cardiac output.¹⁸ Furthermore, early metabolic studies have suggested that CysLTs play a role in cardiac ischemia¹⁹ and only very recently, pharmacologic, genetic, and immunohistochemical data were presented that indicate that 5-lipoxygenase and LTs are involved in atherosclerosis and ischemic heart disease.^16,20,21 Furthermore, CysLTs, formed via transcellular routes along a leukocyte–endothelial cell axis, might elicit coronary vasospasm and inflammatory changes in the vasculature.⁹ For certain contraction-relaxation responses of the vessel wall, CysLT₁R has been implicated in signal transduction, particularly during inflammatory states in the microvasculature,²² and CysLT₁R mRNA is expressed in smooth muscle cells.² Most likely, signaling via CysLT₂R also contributes significantly to the cardiovascular effects of CysLTs, because mRNA has been identified in the heart, including Purkinje cells, smooth muscle cells, and heart muscle.^3–5,23 Interestingly, Hui et al⁶ recently reported that in the mouse heart, CysLT₂R mRNA was also found in certain endothelial cells, in line with our data for HUVECs. Moreover, CysLTs have been found to elicit several specific functional responses in endothelial cells, eg, synthesis of platelet-activating factor,¹⁰ secretion of von Willebrand factor, and surface expression of P-selectin.¹¹ Hence, although the cardiovascular actions of CysLTs are complex and involve both the CysLT₁R and CysLT₂R, our data demonstrate that CysLT₂R is the dominating, functional receptor for CysLTs on HUVECs and might thus be involved in the propagation of local as well as systemic effects of these lipid mediators. Certainly, the CysLT₂R appears to be an interesting target for pharmacologic intervention in cardiovascular diseases, in particular, ischemic heart disease and myocardial infarction.

	Acknowledgments

 
This work was financially supported by the Swedish Research Council (O3X-10350, 19X-05991), the Vårdal Foundation, the European Union (QLG1-CT-2001–01521), Konung Gustav V:s 80-årsfond, the Foundation for Strategic Research, the AFA Health Foundation, the Swedish Association against Rheumatism, the Swedish Heart and Lung Foundation, Systembolagets Research Fund, and the funds of Uggla and Wiberg. The authors thank Andreas Habenicht for technical help and discussions.

	Footnotes

 
*These authors contributed equally to this work.

Received April 2, 2003; accepted May 16, 2003.

	References

Top Abstract Introduction Methods Results and Discussion References

 

1. Funk CD. Prostaglandins and leukotrienes: advances in eicosanoid biology. Science. 2001; 294: 1871–1875.[Abstract/Free Full Text]
2. Lynch KR, O’Neill GP, Liu Q, Im DS, Sawyer N, Metters KM, Coulombe N, Abramovitz M, Figueroa DJ, Zeng Z, Connolly BM, Bai C, Austin CP, Chateauneuf A, Stocco R, Greig GM, Kargman S, Hooks SB, Hosfield E, Williams DL Jr, Ford-Hutchinson AW, Caskey CT, Evans JF. Characterization of the human cysteinyl leukotriene CysLT₁ receptor. Nature. 1999; 399: 789–793.[CrossRef][Medline] [Order article via Infotrieve]
3. Heise CE, O’Dowd BF, Figueroa DJ, Sawyer N, Nguyen T, Im D-S, Stocco R, Bellefeuille JN, Abramovitz M, Cheng R, Williams DL Jr, Zeng Z, Liu Q, Ma L, Clements MK, Coulombe N, Liu Y, Austin CP, George SR, O’Neill GP, Metters KM, Lynch KR, Evans JF. Characterization of the human cysteinyl leukotriene 2 (CysLT₂) receptor. J Biol Chem. 2000; 275: 30531–30536.[Abstract/Free Full Text]
4. Nothacker HP, Wang ZW, Zhu YH, Reinscheid RK, Lin SHS, Civelli O. Molecular cloning and characterization of a second human cysteinyl leukotriene receptor: discovery of a subtype selective agonist. Mol Pharmacol. 2000; 58: 1601–1608.
5. Takasaki J, Kamohara M, Matsumoto M, Saito T, Sugimoto T, Ohishi T, Ishii H, Ota T, Nishikawa T, Kawai Y, Masuho Y, Isogai T, Suzuki Y, Sugano S, Furuichi K. The molecular characterization and tissue distribution of the human cysteinyl leukotriene CysLT₂ receptor. Biochem Biophys Res Commun. 2000; 274: 316–322.[CrossRef][Medline] [Order article via Infotrieve]
6. Hui Y, Yang G, Galczenski H, Figueroa DJ, P Austin CP, Copeland NG, Gilbert DJ, Jenkins NA, Funk CD. The murine cysteinyl leukotriene 2 (CysLT₂) receptor cDNA and genomic cloning, alternative splicing, and in vitro characterization. J Biol Chem. 2001; 276: 47489–47495.[Abstract/Free Full Text]
7. Feinmark SJ, Cannon PJ. Endothelial cell leukotriene C₄ synthesis results from intercellular transfer of leukotriene A₄ synthesized by polymorphonuclear leukocytes. J Biol Chem. 1986; 261: 16466–16472.[Abstract/Free Full Text]
8. Maclouf J, Murphy RC, Henson PM. Transcellular biosynthesis of sulfidopeptide leukotrienes during receptor-mediated stimulation of human neutrophil/platelet mixtures. Blood. 1990; 76: 1838–1844.[Abstract/Free Full Text]
9. Sala A, Aliev GM, Rossoni G, Berti F, Buccellati C, Burnstock G, Folco G, Maclouf J. Morphological and functional changes of coronary vasculature caused by transcellular biosynthesis of sulfidopeptide leukotrienes in isolated heart of rabbit. Blood. 1996; 87: 1824–1832.[Abstract/Free Full Text]
10. McIntyre TM, Zimmerman GA, Prescott SM. Leukotrienes C₄ and D₄ stimulate human endothelial cells to synthesize platelet-activating factor and bind neutrophils. Proc Natl Acad Sci U S A. 1986; 83: 2204–2208.[Abstract/Free Full Text]
11. Datta YH, Romano M, Jacobson BC, Golan DE, Serhan CN, Ewenstein BM. Peptidoleukotrienes are potent agonists of von Willebrand factor secretion and P-selectin surface expression in human umbilical vein endothelial cells. Circulation. 1995; 92: 3304–3311.[Abstract/Free Full Text]
12. Palmblad J, Lerner R, Larsson SH. Signal transduction mechanisms for leukotriene B₄ induced hyperadhesiveness of endothelial cells for neutrophils. J Immunol. 1994; 152: 262–269.[Abstract]
13. Heimburger M, Palmblad JEW. Effects of leukotriene C₄ and D₄, histamine and bradykinin on cytosolic calcium concentrations and adhesiveness of endothelial cells and neutrophils. Clin Exp Immunol. 1996; 103: 454–460.[Medline] [Order article via Infotrieve]
14. Sjöström M, Jakobsson P-J, Heimburger M, Palmblad J, Haeggström JZ. Human umbilical vein endothelial cells generate leukotriene C₄ via microsomal glutathione S-transferase type 2 and express the CysLT₁ receptor. Eur J Biochem. 2001; 268: 2578–2586.[Medline] [Order article via Infotrieve]
15. Romppanen E-L, Savolainen K, Mononen I. Optimal use of the fluorescent PicoGreen dye for quantitative analysis of amplified polymerase chain reaction products on microplate. Anal Biochem. 2000; 279: 111–114.[CrossRef][Medline] [Order article via Infotrieve]
16. Spanbroek R, Gräbner R, Lötzer K, Hildner M, Urbach A, Rühling K, Moos M, Kaiser B, Cohnert TU, Wahlers T, Zieske A, Plenz G, Robenek H, Salbach P, Kühn H, Rådmark O, Samuelsson B, Habenicht AJR. Expanding expression of the 5-lipoxygenase within the arterial wall during human atherogenesis. Proc Natl Acad Sci U S A. 2003; 100: 1238–1243.[Abstract/Free Full Text]
17. Gronert K, Martinsson-Niskanen T, Ravasi S, Chiang N, Serhan CN. Selectivity of recombinant human leukotriene D₄, leukotriene B₄, and lipoxin A₄ receptors with aspirin-triggered 15-epi-LXA₄ and regulation of vascular and inflammatory responses. Am J Pathol. 2001; 158: 3–9.[Abstract/Free Full Text]
18. Smedegård G, Hedqvist P, Dahlén S-E, Revenäs B, Hammarström S, Samuelsson B. Leukotriene C₄ affects pulmonary and cardiovascular dynamics in monkey. Nature. 1982; 295: 327–329.[CrossRef][Medline] [Order article via Infotrieve]
19. Carry M, Korley V, Willerson JT, Weigelt L, Ford-Hutchinson AW, Tagari P. Increased urinary leukotriene excretion in patients with cardiac ischemia: in vivo evidence for 5-lipoxygenase activation. Circulation. 1992; 85: 230–236.[Abstract/Free Full Text]
20. Aiello RJ, Bourassa PA, Lindsey S, Weng WF, Freeman A, Showell HJ. Leukotriene B₄ receptor antagonism reduces monocytic foam cells in mice. Arterioscler Thromb Vasc Biol. 2002; 22: 443–449.[Abstract/Free Full Text]
21. Mehrabian M, Allayee H, Wong J, Shih W, Wang XP, Shaposhnik Z, Funk CD. Identification of 5-lipoxygenase as a major gene contributing to atherosclerosis susceptibility in mice. Circ Res. 2002; 91: 120–126.[Abstract/Free Full Text]
22. Maekawa A, Austen KF, Kanaoka Y. Targeted gene disruption reveals the role of cysteinyl leukotriene 1 receptor in the enhanced vascular permeability of mice undergoing acute inflammatory responses. J Biol Chem. 2002; 277: 20820–20824.[Abstract/Free Full Text]
23. Kamohara M, Takasaki J, Matsumoto M, Matsumoto S-i, Saito T, Soga T, Matsushime H, Furuichi K. Functional characterization of cysteinyl leukotriene CysLT₂ receptor on human coronary artery smooth muscle cells. Biochem Biophys Res Commun. 2001; 287: 1088–1092.[CrossRef][Medline] [Order article via Infotrieve]

This article has been cited by other articles:

				C. Thompson, A. Cloutier, Y. Bosse, C. Poisson, P. Larivee, P. P. McDonald, J. Stankova, and M. Rola-Pleszczynski Signaling by the Cysteinyl-Leukotriene Receptor 2: INVOLVEMENT IN CHEMOKINE GENE TRANSCRIPTION J. Biol. Chem., January 25, 2008; 283(4): 1974 - 1984. [Abstract] [Full Text] [PDF]

				C. Magnusson, R. Ehrnstrom, J. Olsen, and A. Sjolander An Increased Expression of Cysteinyl Leukotriene 2 Receptor in Colorectal Adenocarcinomas Correlates with High Differentiation Cancer Res., October 1, 2007; 67(19): 9190 - 9198. [Abstract] [Full Text] [PDF]

				S. B. Early, E. Barekzi, J. Negri, K. Hise, L. Borish, and J. W. Steinke Concordant Modulation of Cysteinyl Leukotriene Receptor Expression by IL-4 and IFN-{gamma} on Peripheral Immune Cells Am. J. Respir. Cell Mol. Biol., June 1, 2007; 36(6): 715 - 720. [Abstract] [Full Text] [PDF]

				G. Woszczek, L.-Y. Chen, S. Nagineni, S. Alsaaty, A. Harry, C. Logun, R. Pawliczak, and J. H. Shelhamer IFN-{gamma} Induces Cysteinyl Leukotriene Receptor 2 Expression and Enhances the Responsiveness of Human Endothelial Cells to Cysteinyl Leukotrienes J. Immunol., April 15, 2007; 178(8): 5262 - 5270. [Abstract] [Full Text] [PDF]

				H. Qiu, A.-S. Johansson, M. Sjostrom, M. Wan, O. Schroder, J. Palmblad, and J. Z. Haeggstrom Differential induction of BLT receptor expression on human endothelial cells by lipopolysacharide, cytokines, and leukotriene B4 PNAS, May 2, 2006; 103(18): 6913 - 6918. [Abstract] [Full Text] [PDF]

				Y. Hui, Y. Cheng, I. Smalera, W. Jian, L. Goldhahn, G. A. FitzGerald, and C. D. Funk Directed Vascular Expression of Human Cysteinyl Leukotriene 2 Receptor Modulates Endothelial Permeability and Systemic Blood Pressure Circulation, November 23, 2004; 110(21): 3360 - 3366. [Abstract] [Full Text] [PDF]

				T. C. Beller, A. Maekawa, D. S. Friend, K. F. Austen, and Y. Kanaoka Targeted Gene Disruption Reveals the Role of the Cysteinyl Leukotriene 2 Receptor in Increased Vascular Permeability and in Bleomycin-induced Pulmonary Fibrosis in Mice J. Biol. Chem., October 29, 2004; 279(44): 46129 - 46134. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: 23/8/e37    most recent 01.ATV.0000082689.46538.DFv1 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 Sjöström, M. Articles by Haeggström, J. Z. Search for Related Content PubMed PubMed Citation Articles by Sjöström, M. Articles by Haeggström, J. Z. Related Collections Health policy and outcome research Other Ethics and Policy Coagulation inhibitors Endothelium/vascular type/nitric oxide