Originally published online as doi:10.1189/jlb.0808476 on September 15, 2008
Published online before print September 15, 2008
(Journal of Leukocyte Biology. 2008;84:1374-1378.)
© 2008
by Society for Leukocyte Biology
Leukotriene modifiers in the treatment of cardiovascular diseases
Graziano Riccioni*,1,
Valerie Capra
,
Nicolantonio D'Orazio
,
Tonino Bucciarelli and
Lydia A. Bazzano
* Cardiology Unit "San Camillo de Lellis" Hospital, Manfredonia, Foggia, Italy;
Department of Pharmacological Sciences, University of Milan, Milan, Italy;
Human Nutrition, Department of Biomedical Science, University "G. D'Annunzio" Chieti, Italy; and
Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana, USA
1 Correspondence: Via G. De Rogatis, 12, 71016 San Severo (FG), Italia. E-mail: griccioni{at}hotmail.com
ABSTRACT
Cysteinyl-leukotrienes (Cys-LTs) and LTB
4 are potent proinflammatory
mediators derived from arachidonic acid through the 5-lipoxygenase
(5-LO) pathway, which exerts important pharmacological effects
through their interaction with specific receptors: Cys-LT receptors
(CysLT
1 and CysLT
2) and LTB
4 receptors (BLT
1 and BLT
2). Published
evidence justifies a broader role for LT receptor antagonists
(LTRAs), in particular, montelukast, in the treatment of bronchial
asthma, allergic rhinitis, and recently, in cardiocerebrovascular
disease. The actions of Cys-LTs on the cardiovascular (CV) system
are well-documented and include a broad array of activities
with promising therapeutic targets in animal models exploring
the use of selective 5-LO (or 5-LO-activating protein) inhibitors
or dual LO-cycloxygenase-blocking agents in experimentally induced
acute myocardial infarction. The picture that emerges from studies
with LTRAs is more controversial at the moment, and some findings
suggest a role for Cys-LTs in the extension of ischemic damage
and in cardiac dysfunction during reperfusion; others do not.
The aim of this short review is to summarize the state of present
research about LT modifier treatment in CV disease.
Key Words: atherosclerosis • antileukotrienes • stroke • myocardial infarction • ALOX5AP • FLAP • 5-LO
INTRODUCTION
Owing to their anti-inflammatory properties, leukotriene (LT)
modifiers have been one of the primary therapeutics in asthma
management for several years [
1
,
2
]. In the 1970s, cysteinyl
LTs (Cys-LTs) were recognized to have important effects on bronchoconstriction,
mucous hypersecretion, and airway inflammation, and in the late
1990s, LT receptor antagonists (LTRAs) were introduced as antiasthma
medications, and recently, they were also approved for the relief
of symptoms of perennial and seasonal allergic rhinitis [
3
4
5
6
].
Although blocking the inflammatory component of human disease is a long-standing and established concept, the use of LT modifiers in treating the inflammatory component of cardiovascular disease (CVD) has, surprisingly, only been contemplated seriously in the past few years [7
]. However, a recent growing body of evidence suggests a major role for the eicosanoids generated by the 5-lipoxygenase (5-LO) pathway in the pathogenesis and progression of CVD, particularly atherosclerosis, acute myocardial infarction, stroke, aortic aneurysms, and intimal hyperplasia, as LT signaling represents a crucial component in vascular inflammation [8
, 9
] (Fig. 1
). As a result, pharmacological strategies to modulate the LT signaling cascade received renewed interest recently.
BIOCHEMISTRY AND CV EFFECTS
LTs can be grouped into two classes based on the presence or
absence of a thioether-linked peptide [
2
,
10
]. Cys-LTs contain
a thioether linkage: glutathione in LTC
4, cysteinyl-glycine
in LTD
4, and cysteine in LTE
4. In contrast, LTB
4, a dihydroxy
derivative, is devoid of a thioether-linked peptide [
3
]. LTs
are generated at the nuclear membrane of inflammatory myeloid
cells, predominantly granulocytes, macrophages, and mast cells
[
11
], but can also be synthesized by other cells relevant to
the CV system, such as vascular smooth muscle cells (SMCs),
endothelial cells, and platelets [
8
].
Acting in an autocrine/paracrine manner, LTs display strong, proinflammatory activities in CV tissues. LTB4 is a potent chemoattractant for neutrophils and T cells, promotes leukocyte adhesion to vascular endothelium, augments vascular permeability, and promotes vascular SMC proliferation and migration [1
, 8
, 12
13
14
]. Cys-LTs show potent constrictor action on the microvasculature and can enhance permeability, reduce coronary blood flow, decrease myocardial contractility, and reduce cardiac output without affecting the heart rate [15
]. Furthermore, it has been suggested that they are important mediators of ischemia and shock [16
] and can promote migration of human coronary artery SMCs [11
].
Members of the two arms of the LT cascade exert their different biological actions through interaction with specific G protein-coupled receptors: the Cys-LT receptors, CysLT1 and CysLT2, and the LTB4 receptors, BLT1 and BLT2 [17
]. BLT and CysLT subtypes are expressed on vascular SMCs and endothelial cells, and their expression in these cells is highly dependent on transcriptional regulation by pro- and anti-inflammatory mediators [8
].
Experimental evidence from in vitro and in vivo studies suggests that the existence of additional CysLT receptor subtypes and/or the formation of homo- and/or heterodimers may be responsible for identified or additional biological actions [15
]. Furthermore, a few reports suggest that CysLT receptors could also be localized at levels other than the plasma membrane, suggesting an important and unanticipated role for these receptors in cell signaling and function [18
, 19
]. Finally, LTs may play an important role in CVD, also acting as natural nuclear receptor ligands [20
].
A major role for the LT pathway in CVD was suggested by several studies in humans and animal models [21
]. Mehrabian and colleagues [21
, 22
] have demonstrated previously that 5-LO contributes importantly to the atherogenic process and provide strong, presumptive evidence that reduced 5-LO expression is partly responsible for the resistance to atherosclerosis linked to a locus of chromosome 6 in congenic strain mice.
Stimulated polymorphonuclear neutrophils (PMNs) from individuals with a past history of myocardial infarction (MI) produce more LTB4 than do PMNs from controls [23
]. LTB4 and the BLT receptor have been suggested as important components in atherogenic processes [24
, 25
]. In addition, the expression of pathway enzymes as well as LT receptors is increased in atherosclerotic lesions at various stages of development in human aorta, coronary arteries, and carotid arteries [26
, 27
]. Interestingly, recent human genetic studies show that a promoter variant of 5-LO is associated with an increase in carotid intima-media thickness in healthy subjects [28
], and certain 5-LO-activating protein (FLAP) haplotypes have been linked to an almost twofold increased risk of MI or stroke [23
, 29
].
Although as already mentioned, the actions of LTs in the CV system are well-documented and include a broad array of activities [30
, 31
], the picture that emerges from studies with LTRAs is controversial. Indeed, some studies suggest a role for Cys-LTs in the extension of ischemic damage and in cardiac dysfunction during reperfusion [32
33
34
], and others do not [35
36
37
]. However, in the past few years, the use of LTRAs as CV drugs has become a matter of considerable, renewed interest, as the presence of FLAP and LT receptors has been shown in coronary and carotid artery disease specimens [38
, 39
], and correlation has been found among 5-LO, FLAP polymorphisms, and relative risk for MI, stroke, and atherosclerosis [8
, 40
, 41
].
Of particular interest might be cerebral ischemia, where augmented formation of Cys-LTs has been demonstrated, particularly after reperfusion in animal models [42
, 43
], and where Cys-LT levels, higher than normal, have been detected in cerebrospinal fluid of patients within 72 h from the attack [44
]. Indeed, the first evidence of neuroprotection linked to postischemic reduction of Cys-LT levels was obtained by the use of MK-886 in an in vivo model of permanent occlusion of the middle cerebral artery in the rat [45
]. Although the role of LTs in brain injury is not fully understood, data in the literature suggest that LTs might be associated with neuronal injury after hypoxia or trauma [46
]. Both CysLT receptor subtype expression is spatiotemporally related to acute neuronal injury and late astrocyte proliferation [47
48
49
]. The CysLT1 receptor mediates astrocytes proliferation, and the CysLT2 receptor mediates death after oxygen-glucose deprivation [50
]. In addition, selective CysLT1 receptor antagonists might be neuroprotective [51
52
53
54
]. These findings may lead to a previously unexplored, therapeutic potential for LTRAs.
To regulate the effects of LTs pharmacologically, two general approaches have been used with success: inhibition of LT synthesis and antagonism of LT receptors. The LT synthesis inhibitors block key steps in the biosynthetic pathway (5-LO or FLAP) to inhibit production of Cys-LTs and LTB4, whereas the LTRAs selectively block the CysLT1 receptor on target cells. Pharmaceutical agents using both strategies have been approved in the United States, Europe, and other areas.
LT RECEPTOR ANTAGONIST MODIFIERS: SYNTHESIS INHIBITORS
The first committed step in the synthesis of LTs is the oxidation
of arachidonic acid (AA) by 5-LO, and the integral membrane
protein FLAP is an essential partner of 5-LO for this process
[
55
]. FLAP was molecularly identified via a photoaffinity probe
and an affinity gel based on MK-886, a selective LT inhibitor
that has no activity against broken-cell preparations of 5-LO
[
56
]. Several FLAP inhibitors showed efficacy in early clinical
trials in asthma but were not developed commercially for unpublished
reasons [
57
].
Zileuton (ZL) is the only marketed drug with a specific effect on Cys-LT synthesis via inhibition of the 5-LO enzyme, administered orally four times daily (QID) and now available as a twice-daily formulation. It is metabolized by the cytochrome P450 isoenzymes and interacts with other drugs metabolized by these enzymes, and its use is hampered by the QID dosing regimen and the requirement for monitoring liver enzymes. No studies about ZL in CVD treatment are published.
Hakonarson and colleagues [58
] conducted a randomized, placebo-controlled, crossover trial of an inhibitor of FLAP (DG-031) on 268 patients and found a significant, dose-dependent suppression of inflammatory biomarkers (LTB4 and myeloperoxidase) associated with risk of MI. In this study, patients were first randomized to receive 250, 500, and 750 mg/daily DG-031 or placebo for four treatment weeks after a 2-week wash-out period. The FLAP inhibitor DG-031 used in this study (formerly known as BAYx1005) was licensed from Bayer Health Care AG (Leverkusen, Germany). DG-031 is more likely an arachidonate-binding protein/presenter to 5-LO. The drug competes for binding sites on the cell membrane with 5-LO and thus, is a functional, competitive inhibitor.
Recently, an American biotechnology company (VIA Pharmaceuticals, San Francisco, CA, USA) announced an important Phase II-randomized, double-blind, parallel-group, placebo-controlled, dose-ranging study of the effect of VIA-2291 (25, 50, or 100 mg), a potent and reversible 5-LO inhibitor, on vascular inflammation in 191 patients with acute coronary syndrome (ACS).
In the last several years, the FLAP gene (arachidonate FLAP) has been linked to ethnicity-specific risk for MI [59
], stroke, and restenosis, reigniting pharmaceutical interest in this target [60
61
62
]. Although the recent determination of the crystal structure of inhibitor-bound FLAP offers exciting potential for novel FLAP inhibitor design [63
], a recent population sample from central Europe showed no association between specific polymorphisms in the gene for FLAP and risk of MI, a result contrasting previous positive findings [64
].
Two haplotypes (HapA and HapB) in the gene-encoding FLAP, the main regulator of 5-LO, have been associated with a doubling of the risk of MI. Maznyczka and colleagues [61
] have examined whether carriage of HapA or HapB is associated with increased LTB4 production in healthy subjects. In this study, 59 healthy, matched subjects (21 HapA carriers, 20 HapB carriers, and 18 non-A/non-B carriers) with no reported history of CVD were recruited following DNA screening of 1268 subjects from a population-based study. The results showed no difference in the mean level for LTB4 production in the three groups, indicating that should the HapA or the HapB haplotype of FLAP indeed increase CV risk, the mechanism is not simply a result of a systematically observable effect of the haplotype on LTB4 production in response to stimulation.
CONCLUSION
LTs are potent, inflammatory mediators synthesized within the
CV system through the 5-LO pathway of AA metabolism. Recently,
BLT receptors were found on human vascular SMCs, inducing their
migration and proliferation. Cys-LTs are vasoconstrictors and
induce an endothelium-dependent vascular response through the
CysLT
1 and CysLT
2 receptor subtypes. Taken together, experimental
and genetic studies suggest a major role for LTs in atherosclerosis
and in its ischemic complications such as ACS and stroke [
65
].
Furthermore, the effects on vascular SMCs suggest a role in the vascular remodeling observed after coronary angioplasty, as well as in aortic aneurysm. Further experimental and clinical studies are needed to determine the potential therapeutic strategies targeting the LT pathway in CVD [66
, 67
]. The recent evidence regarding application of LT modifiers has greatly increased the potential for their use in CV and cerebrovascular disease. The exact role of LTRAs in disease management still continues to evolve. Large-scale, controlled trials are needed to determine the effectiveness and safety deriving from treatment with LT modifiers in CVD [68
].
Received August 13, 2008;
accepted August 13, 2008.
REFERENCES
1 - Peters-Golden, M., Henderson, W. R., Jr (2007) Leukotrienes N. Engl. J. Med. 357,1841-1854[Free Full Text]
2 - Samuelsson, B., Dahlen, S. E., Lindgren, J. A., Rouzer, C. A., Serhan, C. N. (1987) Leukotrienes and lipoxins: structures, biosynthesis, and biological effects Science 237,1171-1176[Abstract/Free Full Text]
3 - Capra, V., Ambrosio, M., Riccioni, G., Rovati, G. E. (2006) Cysteinyl-leukotriene receptor antagonists: present situation and future opportunities Curr. Med. Chem. 13,3213-3226[Medline]
4 - Coleman, R. A., Eglen, R. M., Jones, R. L. (1995) Prostanoid and leukotriene receptors: a progress report from the IUPHAR working parties on classification and nomenclature Adv. Prostaglandin Thromboxane Leukot. Res. 23,283-285[Medline]
5 - Riccioni, G., Santilli, F., D'Orazio, N., Sensi, S., Spoltore, R., De Benedictis, M., Guagnano, M. T., Di Ilio, C., Della Vecchia, R. (2002) The role of antileukotrienes in the treatment of asthma Int. J. Immunopathol. Pharmacol. 15,171-182[Medline]
6 - Piper, P. J. (1984) Formation and actions of leukotrienes Physiol. Rev. 64,744-761[Free Full Text]
7 - Funk, C. D. (2005) Leukotriene modifiers as potential therapeutics for cardiovascular disease Nat. Rev. Drug Discov. 4,664-672[CrossRef][Medline]
8 - Back, M. (2007) Leukotriene receptors: crucial components in vascular inflammation ScientificWorldJournal 7,1422-1439[CrossRef][Medline]
9 - Funk, C. D., Cyrus, T. (2001) 12/15-Lipoxygenase, oxidative modification of LDL and atherogenesis Trends Cardiovasc. Med. 11,116-124[CrossRef][Medline]
10 - Funk, C. D. (2001) Prostaglandins and leukotrienes: advances in eicosanoid biology Science 294,1871-1875[Abstract/Free Full Text]
11 - Nicosia, S., Capra, V., Rovati, G. E. (2001) Leukotrienes as mediators of asthma Pulm. Pharmacol. Ther. 14,3-19[CrossRef][Medline]
12 - Ford-Hutchinson, A. W. (1990) Leukotriene B4 in inflammation Crit. Rev. Immunol. 10,1-12[Medline]
13 - Lewis, R. A., Austen, K. F., Sobermann, R. J. (1990) Leukotrienes and other products of the 5-lipoxygenase pathway. Biochemistry and relation to pathobiology in human diseases N. Engl. J. Med. 323,645-655[Medline]
14 - Gimbrone, M. A., Jr, Brock, A. F., Schafer, A. I. (1984) Leukotriene B4 stimulates polymorphonuclear leukocyte adhesion to cultured vascular endothelial cells J. Clin. Invest. 74,1552-1555[Medline]
15 - Capra, V., Thompson, M. D., Sala, A., Cole, D. E., Folco, G., Rovati, G. E. (2007) Cysteinyl-leukotrienes and their receptors in asthma and other inflammatory diseases: critical update and emerging trends Med. Res. Rev. 27,469-527[CrossRef][Medline]
16 - Lefer, A. M. (1988) Thromboxane A2 and leukotrienes are eicosanoid mediators of shock and ischemic disorders Prog. Clin. Biol. Res. 264,101-114[Medline]
17 - Brink, C., Dahlen, S. E., Drazen, J., Evans, J. F., Hay, D. W., Nicosia, S., Serhan, C. N., Shimnizu, T., Yokomizo, T. (2003) International Union of Pharmacology XXXVII. Nomenclature for leukotriene and lipoxin receptors Pharmacol. Rev. 55,195-227[Abstract/Free Full Text]
18 - Bandeira-Melo, C., Woods, L. J., Phoofolo, M., Weller, P. F. (2002) Intracrine cysteinyl leukotriene receptor-mediated signaling of eosinophil vesicular transport-mediated interleukin-4 secretion J. Exp. Med. 196,841-850[Abstract/Free Full Text]
19 - Nielsen, C. K., Campbell, J. I., Ohd, J. F., Morgelin, M., Riesbeck, K., Landberg, G., Sjolander, A. (2005) A novel localization of the G-protein-coupled CysLT1 receptor in the nucleus of colorectal adenocarcinoma cells Cancer Res. 65,732-742[Abstract/Free Full Text]
20 - Devchand, P. R., Keller, H., Peters, J. M., Vazquez, M., Gonzalez, F. J., Wahli, W. (1996) The PPAR
-leukotriene B4 pathway to inflammation control Nature 384,39-43[CrossRef][Medline] 21 - Ghazalpour, A., Wang, X., Lusis, A. J., Mehrabian, M. (2006) Complex inheritance of the 5-lipoxygenase locus influencing atherosclerosis in mice Genetics 173,943-951[Abstract/Free Full Text]
22 - Bäck, M. (2007) Leukotriene receptors: crucial components in vascular inflammation ScientificWorldJournal 7,1422-1439[CrossRef][Medline]
23 - Helgadottir, A., Manolescu, A., Thorleifsson, G., Gretarsdottir, S., Jonsdottir, H., Thorsteinsdottir, U., Samani, N. J., Gudmundsson, G., Grant, S. F., Thorgeirsson, G., et al (2004) The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke Nat. Genet. 36,233-239[CrossRef][Medline]
24 - Subbarao, K., Jala, V. R., Mathis, S., Suttles, J., Zacharias, W., Ahamed, J., Ali, H., Tseng, M. T., Haribabu, B. (2004) Role of leukotriene B4 receptors in the development of atherosclerosis: potential mechanisms Arterioscler. Thromb. Vasc. Biol. 24,369-375[Abstract/Free Full Text]
25 - Zhao, L., Moos, M. P., Gräbner, R., Pédrono, F., Fan, J., Kaiser, B., John, N., Schmidt, S., Spanbroek, R., Lötzer, K., Huang, L., Cui, J., Rader, D. J., Evans, J. F., Habenicht, A. J., Funk, C. D. (2004) The 5-lipoxygenase pathway promotes pathogenesis of hyperlipidemia-dependent aortic aneurysm Nat. Med. 10,966-973[CrossRef][Medline]
26 - Spanbroek, R., Grabner, R., Lotzer, K., Hildner, M., Urbach, A., Ruhling, K., Moos, M. P., Kaiser, B., Cohenert, T. U., Wahlers, T., Zieske, A., Plenz, G., Robenek, H., Salbach, P., Kuhn, H., Radmark, O., Samuelsson, B., Habenicht, A. J. (2003) Expanding expression of the 5-lipoxygenase pathway within the arterial wall during human atherogenesis Proc. Natl. Acad. Sci. USA 100,1238-1243[Abstract/Free Full Text]
27 - Qiu, H., Gabrielsen, A., Agardh, H. E., Wan, M., Wetterholm, A., Wong, C. H., Hedin, U., Swedenborg, J., Hansson, G. K., Samuelsson, B., Paulsson-Berne, G., Haeggström, J. Z. (2006) Expression of 5-lipoxygenase and leukotriene A4 hydrolase in human atherosclerotic lesions correlates with symptoms of plaque instability Proc. Natl. Acad. Sci. USA 103,8161-8166[Abstract/Free Full Text]
28 - Dwyer, J. H., Allayee, H., Dwyer, K. M., Fan, J., Wu, H., Mar, R., Lusis, A. J., Mehrabian, M. (2004) Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis N. Engl. J. Med. 350,29-37[Abstract/Free Full Text]
29 - Helgadottir, A., Gretarsdottir, S., St Clair, D., Manolescu, A., Cheung, J., Thorleifsson, G., Pasdar, A., Grant, S. F., Whalley, L. J., Hakonarson, H., Thorsteinsdottir, U., Kong, A., Gulcher, J., Stafansson, K., MacLeod, M. J. (2005) Association between the gene encoding 5-lipoxygenase-activating protein and stroke replicated in a Scottish population Am. J. Hum. Genet. 76,505-509[CrossRef][Medline]
30 - Lefer, A. M. (1988) Thromboxane A2 and leukotrienes are eicosanoid mediators of shock and ischemic disorders Prog. Clin. Biol. Res. 264,101-114[Medline]
31 - Letts, L. G. (1987) Leukotrienes: role in cardiovascular physiology Cardiovasc. Clin. 18,101-113[Medline]
32 - Hahn, R. A., MacDonald, B. R., Simpson, P. J., Wang, L., Towner, R. D., Ho, P. P., Goodwin, M., Breau, A. P., Suarez, T., Mihelich, E. D. (1991) Characterization of LY233569 on 5-lipoxygenase and reperfusion injury of ischemic myocardium J. Pharmacol. Exp. Ther. 256,94-102[Abstract/Free Full Text]
33 - Hock, C. E., Beck, L. D., Papa, L. A. (1992) Peptide leukotriene receptor antagonism in myocardial ischemia and reperfusion Cardiovasc. Res. 26,1206-1211[Abstract/Free Full Text]
34 - Mullane, K., Hatala, M. A., Kraemer, R., Sessa, W., Westlin, W. (1987) Myocardial salvage induced by REV-5901: an inhibitor and antagonist of the leukotrienes J. Cardiovasc. Pharmacol. 10,398-406[Medline]
35 - Hahn, R. A., MacDonald, B. R., Morgan, E., Potts, B. D., Parli, C. J., Rinkema, L. E., Whitesitt, C. A., Marshall, W. S. (1992) Evaluation of LY203647 on cardiovascular leukotriene D4 receptors and myocardial reperfusion injury J. Pharmacol. Exp. Ther. 260,979-989[Abstract/Free Full Text]
36 - Ito, B. R., Roth, D. M., Engler, R. L. (1990) Thromboxane A2 and peptidoleukotrienes contribute to the myocardial ischemia and contractile dysfunction in response to intracoronary infusion of complement C5a in pigs Circ. Res. 66,596-607[Abstract/Free Full Text]
37 - Ito, T., Toki, Y., Hieda, Y., Okumura, K., Hashimoto, H., Ogawa, K., Satake, T. (1989) Protective effects of a thromboxane synthetase inhibitor, a thromboxane antagonist, a lipoxygenase inhibitor and a leukotriene C4, D4 antagonist on myocardial injury caused by acute myocardial infarction in the canine heart Jpn. Circ. J. 53,1115-1121[Medline]
38 - Amsterdam, E. A., Pan, H. L., Rendig, S. V., Symons, J. D., Fletcher, M. P., Longhurst, J. C. (1993) Limitation of myocardial infarct size in pigs with a dual lipoxygenase-cyclooxygenase blocking agent by inhibition of neutrophil activity without reduction of neutrophil migration J. Am. Coll. Cardiol. 22,1738-1744[Abstract]
39 - Kamohara, M., Takasaki, J., Matsumoto, M., Matsumoto, S., Saito, T., Soga, T., Matsushime, H., Furuichi, K. (2001) Functional characterization of cysteinyl leukotriene CysLT(2) receptor on human coronary artery smooth muscle cells Biochem. Biophys. Res. Commun. 287,1088-1092[CrossRef][Medline]
40 - Dwyer, J. H., Allayee, H., Dwyer, K. M., Fan, J., Wu, H., Mar, R., Lusis, A. J., Mehrabian, M. (2004) Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis N. Engl. J. Med. 350,29-37[Abstract/Free Full Text]
41 - Bevan, S. (2008) Genetic variation in members of the leukotriene biosynthesis pathway confer an increase risk of ischemic stroke: a replication study in two independent populations Stroke 39,1109-1114[Abstract/Free Full Text]
42 - Moskowitz, M. A., Kiwak, K. J., Hekimian, K., Levine, L. (1984) Synthesis of compounds with properties of leukotrienes C4 and D4 in gerbil brains after ischemia and reperfusion Science 224,886-889[Abstract/Free Full Text]
43 - Minamisawa, H., Terashi, A., Katayama, Y., Kanda, Y., Shimizu, J., Shiratori, T., Inamura, K., Kaseki, H., Yoshino, Y. (1988) Brain eicosanoid levels in spontaneously hypertensive rats after ischemia with reperfusion: leukotriene C4 as a possible cause of cerebral edema Stroke 19,372-377[Abstract/Free Full Text]
44 - Aktan, S., Aykut, C., Ercan, S. (1991) Leukotriene C4 and prostaglandin E2 activities in the serum and cerebrospinal fluid during acute cerebral ischemia Prostaglandins Leukot. Essent. Fatty Acids 43,247-249[CrossRef][Medline]
45 - Ciceri, P., Rabuffetti, M., Monopoli, M., Nicosia, S. (2001) Production of leukotrienes in a model of focal cerebral ischaemia in the rat Br. J. Pharmacol. 133,1323-1329[CrossRef][Medline]
46 - Bonventre, J. V., Huang, Z., Taheri, M. R., O'Leary, E., Li, E., Moskowitz, M. A., Sapirstein, A. (1997) Reduced fertility and postischemic brain injury in mice deficient in cytosolic phospholipase A2 Nature 390,622-625[CrossRef][Medline]
47 - Fang, S. H., Wei, E. Q., Zhou, Y., Wang, M. L., Zhang, W. P., Yu, G. L., Chu, L. S., Chen, Z. (2006) Increased expression of cysteinyl leukotriene receptor-1 in the brain mediates neuronal damage and astrogliosis after focal cerebral ischemia in rats Neuroscience 140,969-979[CrossRef][Medline]
48 - Fang, S. H., Zhou, Y., Chu, L. S., Zhang, W. P., Wang, M. L., Yu, G. L., Peng, F., Wei, E. Q. (2007) Spatio-temporal expression of cysteinyl leukotriene receptor-2 mRNA in rat brain after focal cerebral ischemia Neurosci. Lett. 412,78-83[CrossRef][Medline]
49 - Zhang, Y. J., Zhang, L., Ye, Y. L., Fang, S. H., Zhou, Y., Zhang, W. P., Lu, Y. B., Wei, E. Q. (2006) Cysteinyl leukotriene receptors CysLT1 and CysLT2 are upregulated in acute neuronal injury after focal cerebral ischemia in mice Acta Pharmacol. Sin. 27,1553-1560[CrossRef][Medline]
50 - Huang, X. J., Zhang, W. P., Li, C. T., Shi, W. Z., Fang, S. H., Lu, Y. B., Chen, Z., Wei, E. Q. (2008) Activation of CysLT receptors induces astrocyte proliferation and death after oxygen-glucose deprivation Glia 56,27-37[CrossRef][Medline]
51 - Yu, G. L., Wei, E. Q., Zhang, S. H., Xu, H. M., Chu, L. S., Zhang, W. P., Zhang, Q., Chen, Z., Mei, R. H., Zhao, M. H. (2005) Montelukast, a cysteinyl leukotriene receptor-1 antagonist, dose- and time-dependently protects against focal cerebral ischemia in mice Pharmacology 73,31-40[CrossRef][Medline]
52 - Yu, G. L., Wie, E. Q., Wang, M. L., Zhang, W. P., Zhang, S. H., Wenig, J. Q., Chu, L. S., Fang, S. H., Zhou, Y., Chen, Z., Zhang, Q., Zhang, L. H. (2005) Pranlukast, a cysteinyl leukotriene receptor-1 antagonist, protects against chronic ischemic brain injury and inhibits the glial scar formation in mice Brain Res. 1053,116-125[CrossRef][Medline]
53 - Qian, X. D., Qian, X. D., Wie, E. Q., Zhang, L., Sheng, W. W., Wang, M. L., Zhang, W. P., Chen, Z. (2006) Pranlukast, a cysteinyl leukotriene receptor 1 antagonist, protects mice against brain cold injury Eur. J. Pharmacol. 549,35-40[CrossRef][Medline]
54 - Ciana, P., Fumagalli, M., Trincavelli, M. L., Verderio, C., Rosa, P., Lecca, D., Ferrario, S., Parravicini, C., Capra, V., Gelosa, P., Guerrini, U., Belcredito, S., Cimino, M., Sironi, L., Tremoli, E., Rovati, G. E., Martini, C., Abbracchio, M. P. (2006) The orphan receptor GPR17 identified as a new dual uracil nucleotides/cysteinyl-leukotrienes receptor EMBO J. 25,4615-4627[CrossRef][Medline]
55 - Xu, S., McKeever, B. M., Wisniewski, D., Miller, D. K., Spencer, R. H., Chu, L., Ujjainwalla, F., Yamin, T. T., Evans, J. F., Becker, J. W., Ferguson, A. D. (2007) Expression, purification and crystallization of human 5-lipoxygenase-activating protein with leukotriene-biosynthesis inhibitors Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 63,1054-1057[CrossRef][Medline]
56 - Ferguson, A. D., McKeever, B. M., Xu, S., Wisniewski, D., Miller, D. K., Yamin, T. T., Spencer, R. H., Chu, L., Ujjainwalla, F., Cunningham, B. R., Evans, J. F., Becker, J. W. (2007) Crystal structure of inhibitor-bound human 5-lipoxygenase-activating protein Science 317,510-512[Abstract/Free Full Text]
57 - Peters-Golden, M., Brock, T. G. (2003) 5-Lipoxygenase and FLAP Prostaglandins Leukot. Essent. Fatty Acids 69,99-109[CrossRef][Medline]
58 - Hakonarson, H., Thorvaldsson, S., Helgadottir, A., Gudbjartsson, D., Zink, F., Andresdottir, M., Manolescu, A., Arnar, D. O., Andersen, K., Sigurdsson, A., et al (2005) Effects of a 5-lipoxygenase-activating protein inhibitor on biomarkers associated with risk of myocardial infarction: a randomized trial JAMA 293,2245-2256[Abstract/Free Full Text]
59 - Helgadottir, A., Manolescu, A., Helgason, A., Thorleifsson, G., Thorsteinsdottir, U., Gudbjartsson, D. F., Gretarsdottir, S., Magnusson, K. P., Gudmundsson, G., Hicks, A., et al (2006) A variant of the gene encoding leukotriene A4 hydrolase confers ethnicity-specific risk of myocardial infarction Nat. Genet. 38,68-74[Medline]
60 - Zee, R. Y., Cheng, S., Hegener, H. H., Erlich, H. A., Ridker, P. M. (2006) Genetic variants of arachidonate 5-lipoxygenase-activating protein, and risk of incident myocardial infarction and ischemic stroke: a nested case-control approach Stroke 37,2007-2011[Abstract/Free Full Text]
61 - Maznyczka, A., Mangino, M., Whittaker, A., Braund, P., Palmer, T., Tobin, M., Goodall, A. H., Bradding, P., Samani, N. J. (2007) Leukotriene B4 production in healthy subjects carrying variants of the arachidonate 5-lipoxygenase-activating protein gene associated with a risk of myocardial infarction Clin. Sci. 112,411-416[CrossRef][Medline]
62 - Girelli, D., Martinelli, N., Trabetti, E., Olivieri, O., Cavallari, U., Malerba, G., Busti, F., Friso, S., Pizzolo, F., Pignatti, P. F., Corrocher, R. (2007) ALOX5AP gene variants and risk of coronary artery disease: an angiography-based study Eur. J. Hum. Genet. 15,959-966[CrossRef][Medline]
63 - Koch, W., Hoppmann, P., Mueller, J. C., Schömig, A., Kastrati, A. (2007) No association of polymorphisms in the gene encoding 5-lipoxygenase-activating protein and myocardial infarction in a large central European population Genet. Med. 9,123-129[Medline]
64 - Evans, J. F., Ferguson, A. D., Mosley, R. T., Hutchinson, J. H. (2008) What’s all the FLAP about?: 5-lipoxygenase-activating protein inhibitors for inflammatory diseases Trends Pharmacol. Sci. 29,72-78[CrossRef][Medline]
65 - Hakonarson, H. (2006) Role of FLAP and PDE4D in myocardial infarction and stroke: target discovery and future treatment options Curr. Treat. Options. Cardiovasc. Med. 8,183-192[CrossRef][Medline]
66 - Mocatta, T. J., Pilbrow, A. P., Cameron, V. A., Senthilmohan, R., Frampton, C. M., Richards, A. M., Winterbourn, C. C. (2007) Plasma concentrations of myeloperoxidase predict mortality after myocardial infarction J. Am. Coll. Cardiol. 49,1993-2000[Abstract/Free Full Text]
67 - Khan, S. Q., Kelly, D., Quinn, P., Davies, J. E., Ng, L. L. (2007) Myeloperoxidase aids prognostication together with N-terminal pro-B-type natriuretic peptide in high-risk patients with acute ST elevation myocardial infarction Heart 93,826-831[Abstract/Free Full Text]
68 - Back, M. (2006) Leukotrienes: potential therapeutic target in cardiovascular diseases Bull. Acad. Natl. Med. 190,1511-1518[Medline]
TOP
ABSTRACT
INTRODUCTION
