Leukotrienes

Peters‐Golden, Marc; Henderson, William R.

doi:10.1056/nejmra071371

Cited by 978 publications

(1,024 citation statements)

References 116 publications

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“…1) inhibits intimal hyperplasia after vascular injury in different animal models [5,39]. Recently, it was discovered that SMCs within human atherosclerotic lesions also express receptors for LTB 4 [38,40], mediating proliferation and migration of coronary artery SMCs [40]. The important signaling through these receptors has been supported by findings in ApoE −/− mice with a targeted BLT 1 receptor, which have fewer SMCs in their lesions [38].…”

Section: Intimal Hyperplasiamentioning

confidence: 98%

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Leukotriene Signaling in Atherosclerosis and Ischemia

Bäck

2008

Cardiovasc Drugs Ther

121

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Section: Intimal Hyperplasiamentioning

confidence: 98%

“…The two arms of the LT pathway have distinct receptors referred to as BLT receptors (activated by LTB 4 ) and CysLT receptors (activated by the cysteinyl-LTs), respectively ( Fig. 1) [5].…”

Section: Leukotriene Receptorsmentioning

confidence: 99%

Leukotriene Signaling in Atherosclerosis and Ischemia

Bäck

2008

Cardiovasc Drugs Ther

121

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“…This inhibition has been achieved with ramatroban, marketed for allergic rhinitis, which blocks the TP receptor (this receptor binds thromboxane A2) and the chemoattractant receptor-homologous molecule that is expressed on Th2 lymphocytes (CRTH2; receptor for prostaglandin D2) in parallel 115 . Modulation of leukotriene action has also been shown to be effective against asthma and allergic rhinitis: zileton targets 5-LO with a limited potency, whereas montelukast, pranlukast and zafirlukast interfere with the action of cysteinyl leukotrienes (leukotrienes C4, D4 and E4) on cysteinyl leukotriene-1 and -2 receptors 116,117 .…”

Section: Therapeutic Opportunitiesmentioning

confidence: 99%

Lipid signalling in disease

Wymann

Schneiter

2008

Nat Rev Mol Cell Biol

1,128

906

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“…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.…”

mentioning

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

161

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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Leukotrienes

Cited by 978 publications

References 116 publications

Leukotriene Signaling in Atherosclerosis and Ischemia

Leukotriene Signaling in Atherosclerosis and Ischemia

Lipid signalling in disease

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

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