Functional Characterization of Cysteinyl Leukotriene CysLT2 Receptor on Human Coronary Artery Smooth Muscle Cells

Kamohara, Masazumi; Takasaki, Jun; Matsumoto, Mitsuyuki; Matsumoto, S.; Saito, Tetsu; Soga, Tsunehiko; Matsushime, Hitoshi; Furuichi, Kiyoshi

doi:10.1006/bbrc.2001.5695

Cited by 61 publications

(56 citation statements)

References 17 publications

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“…Another possible explanation relates to the fact that MK 571 is a specific antagonist of cys-LT receptor 1, but not of cys-LT receptor 2. As evidence has implicated cys-LT receptor 2 in certain vascular events (36), it is possible that some of the vascular effects of cys-LTs in sepsis likewise are mediated via cys-LT receptor 2; further studies are required to define a possible role of cys-LT receptor 2 in sepsis. Finally, although LTB 4 does not exert direct effects on vascular responses, we cannot rule out the possibility of indirect vascular effects of this mediator.…”

Section: Discussionmentioning

confidence: 99%

Opposing and Hierarchical Roles of Leukotrienes in Local Innate Immune versus Vascular Responses in a Model of Sepsis

Benjamim¹,

Canetti

Cunha

et al. 2005

The Journal of Immunology

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The 5-lipoxygenase (5-LO)-derived leukotrienes (LTs) influence both local innate immunity and vascular responses, but the relative importance of effects on these two processes in sepsis is unknown. In a cecal ligation and puncture model of peritonitis with severe sepsis, 5-LO−/− mice showed a reduction in peritoneal neutrophil accumulation and an increase in the number of bacteria in the peritoneal cavity. Despite this impairment of local innate immunity, the null mice exhibited a marked improvement in survival, and this protection was also seen in wild-type animals treated with the LT synthesis inhibitor MK 886. A survival advantage in severe sepsis was also observed in mice treated with the cysteinyl-LT receptor antagonist MK 571, but not with the LTB4 receptor antagonist CP 105, 696. Protection in the 5-LO−/− mice was associated with reduced vascular leak and serum lactate levels. Moreover, wild-type mice treated with MK 571 exhibited less sepsis-induced hypotension. These data demonstrate opposing effects of cysteinyl-LTs on innate immune vs hemodynamic responses, demonstrating protective effects on local immunity and deleterious effects on the vasculature. They also suggest the possible therapeutic utility of targeting vascular events in sepsis with cysteinyl-LT blockade.

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Section: Discussionmentioning

confidence: 99%

Opposing and Hierarchical Roles of Leukotrienes in Local Innate Immune versus Vascular Responses in a Model of Sepsis

Benjamim¹,

Canetti

Cunha

et al. 2005

The Journal of Immunology

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“…A quantitative RT-PCR analysis in the mouse revealed that GPR99 mRNA is highly expressed in kidney, testis, and smooth muscle (23). Given that CysLT 1 R and CysLT 2 R are also expressed on smooth muscle cells in airways and blood vessels (3,4,28,29), expression and function of GPR99 on smooth muscle may be affected by the presence of CysLT 1 R and CysLT 2 R. LTE 4 has a sufficient biologic half-life to be excreted into the urine (30), and urinary LTE 4 excretion is significantly increased in spontaneous acute asthma flares (22). Asthmatic individuals show LTE 4 -induced bronchoconstriction as an aerosol in the same concentration range as LTD 4 and LTC 4 (31,32), and LTE 4 potentiates airway hyperresponsiveness to histamine (33).…”

Section: Gpr99 Mediates Lte 4 -Induced Ear Edema In the Cysltr1/ Cysltr2mentioning

confidence: 99%

Identification of GPR99 Protein as a Potential Third Cysteinyl Leukotriene Receptor with a Preference for Leukotriene E4 Ligand

Kanaoka

Maekawa

Austen

2013

Journal of Biological Chemistry

160

154

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Background: A most stable cysteinyl leukotriene, LTE 4 , mediates vascular permeability in mice lacking the two known receptors. Results: GPR99 deficiency abolishes LTE 4 -induced vascular permeability in mice also lacking the two known receptors. Conclusion: GPR99 is a potential third cysteinyl leukotriene receptor. Significance: GPR99 may be a therapeutic target for inflammatory diseases.The cysteinyl leukotrienes (cys-LTs), leukotriene C 4 (LTC 4 ), a conjugation product of glutathione and eicosatetraenoic acid, and its metabolites, LTD 4 and LTE 4 , are lipid mediators of smooth muscle constriction and inflammation in asthma. LTD 4 is the most potent ligand for the type 1 cys-LT receptor (CysLT 1 R), and LTC 4 and LTD 4 have similar lesser potency for CysLT 2 R, whereas LTE 4 has little potency for either receptor. Cysltr1/Cysltr2 ؊/؊ mice, lacking the two defined receptors, exhibited a comparable dose-dependent vascular leak to intradermal injection of LTC 4 or LTD 4 and an augmented response to LTE 4 as compared with WT mice. As LTE 4 retains a cysteine residue and might provide recognition via a dicarboxylic acid structure, we screened cDNAs within the P2Y nucleotide receptor family containing CysLTRs and dicarboxylic acid receptors with trans-activator reporter gene assays. GPR99, previously described as an oxoglutarate receptor (Oxgr1), showed both a functional and a binding response to LTE 4 in these transfectants. We generated Gpr99 ؊/؊ and Gpr99/Cysltr1/Cysltr2 ؊/؊ mice for comparison with WT and Cysltr1/Cysltr2 ؊/؊ mice. Strikingly, GPR99 deficiency in the Cysltr1/Cysltr2 ؊/؊ mice virtually eliminated the vascular leak in response to the cys-LT ligands, indicating GPR99 as a potential CysLT 3 R active in the Cysltr1/Cysltr2 ؊/؊ mice. Importantly, the Gpr99 ؊/؊ mice showed a dose-dependent loss of LTE 4 -mediated vascular permeability, but not to LTC 4 or LTD 4 , revealing a preference of GPR99 for LTE 4 even when CysLT 1 R is present. As LTE 4 is the predominant cys-LT species in inflamed tissues, GPR99 may provide a new therapeutic target.Leukotriene C 4 (LTC 4 ), 2 LTD 4 , and LTE 4 , collectively called cysteinyl leukotrienes (cys-LTs), are proinflammatory mediators derived from arachidonic acid through the 5-lipoxygenase/ LTC 4 synthase pathway (1, 2). Intracellularly synthesized LTC 4 is exported via multidrug resistance-associated proteins and is rapidly metabolized in the extracellular space by cleavage removal of glutamic acid and then glycine to LTD 4 and LTE 4 , respectively. The type 1 cys-LT receptor (CysLT 1 R) is the high affinity receptor for LTD 4 , whereas the type 2 receptor (CysLT 2 R) can bind both LTC 4 and LTD 4 with one-log less affinity than that of CysLT 1 R for LTD 4 in transfected cells (3, 4). The cys-LTs are mediators of bronchial asthma on the basis of their potent bronchoconstrictive activity via the CysLT 1 R in pharmacologic studies and the clinical effectiveness of CysLT 1 R antagonists (5, 6).LTE 4 , the most abundant cys-LT at sites of inflammation due to its stab...

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“…Interestingly, these studies provided the important information that the hemodynamic e ects of mediators depend on both the underlying cardiovascular conditions and pharmacologic treatment (e. g., H 2 blockade). Using speci c antagonists of CysLT 1 and CysLT 2 [58] it will be possible to assess the each receptor's contribution to the cardiovascular e ects of these vasoactive mediators. Immunologically activated human mast cells synthesize PAF [33], which can play a role in human [34] and experimental anaphylaxis [59].…”

Section: Resultsmentioning

confidence: 99%

“…us, small doses of cysteinyl leukotrienes may induce both an early transient fall in mean arterial pressure, with secondary sympatho-adrenergic activation, and a HHMC ,human cardiac mast cells; C3aR, C3a receptor; C5aR, C5a receptor; IgE, immunoglobulin E; SCF, stem cell factor; TNF-α, tumornecrosis factor α; KIT, tyrosine kinase receptor; PGD2, prostaglandine 2; LTC4, cysteinyl leukotriene C4; PAF, platelet-activating factor Review Article Human heart as a shock organ in anaphylaxis later increase in small coronary arteriolar resistance. Although high levels of cysteinyl leukotriene receptor CysLT 2 mRNA were detected in the human heart and coronary artery, while cysteinyl leukotriene receptor CysLT 1 mRNA was barely detectable [58], it is not clear which receptor was involved in these cardiovascular e ects.…”

Section: Cardiovascular E Ects Of Cysteinyl Leukotrienes In Manmentioning

confidence: 98%

The Human Heart As a Shock Organ in Anaphylaxis

Marone

Bova

Detoraki

et al. 2004

Novartis Foundation Symposia

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Functional Characterization of Cysteinyl Leukotriene CysLT2 Receptor on Human Coronary Artery Smooth Muscle Cells

Cited by 61 publications

References 17 publications

Opposing and Hierarchical Roles of Leukotrienes in Local Innate Immune versus Vascular Responses in a Model of Sepsis

Opposing and Hierarchical Roles of Leukotrienes in Local Innate Immune versus Vascular Responses in a Model of Sepsis

Identification of GPR99 Protein as a Potential Third Cysteinyl Leukotriene Receptor with a Preference for Leukotriene E4 Ligand

The Human Heart As a Shock Organ in Anaphylaxis

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