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Inflammatory signaling through leukotriene receptors in atherosclerosis

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Abstract

The atherosclerotic lesion is a site of local production of the lipid-derived inflammatory mediators known as leukotrienes. This production leads to autocrine and paracrine activation of leukotriene receptors of the BLT and CysLT receptor subtypes expressed on leukocytes and structural cells within the vascular wall. Studies in mice, rats, and rabbits have revealed a key role for leukotriene signaling in atherosclerosis, abdominal aneurysms, and intimal hyperplasia. In addition, a major atherosclerotic immune activation may be leukotriene-dependent through mediation of leukocyte cross-talk within the atherosclerotic lesion. Furthermore, leukotrienes induce endothelium-dependent and independent vascular responses. Finally, recent findings indicate that leukotriene-dependent degradation of the extracellular matrix may link this pathway to atherosclerotic plaque instability. Taken together, the leukotriene pathway may represent a putative therapeutic target in the treatment of atherosclerotic vessel disease.

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References and Recommended Reading

  1. Peters-Golden M, Henderson WR Jr: Leukotrienes. N Engl J Med 2007, 357:1841–1854.

    Article  PubMed  CAS  Google Scholar 

  2. Allen S, Dashwood M, Morrison K, Yacoub M: Differential leukotriene constrictor responses in human atherosclerotic coronary arteries. Circulation 1998, 97:2406–2413.

    PubMed  CAS  Google Scholar 

  3. Piomelli D, Feinmark SJ, Cannon PJ: Leukotriene biosynthesis by canine and human coronary arteries. J Pharmacol Exp Ther 1987, 241:763–770.

    PubMed  CAS  Google Scholar 

  4. Carry M, Korley V, Willerson JT, et al.: Increased urinary leukotriene excretion in patients with cardiac ischemia. In vivo evidence for 5-lipoxygenase activation. Circulation 1992, 85:230–236.

    PubMed  CAS  Google Scholar 

  5. Helgadottir A, Manolescu A, Thorleifsson G, et al.: The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke. Nat Genet 2004, 36:233–239.

    Article  PubMed  CAS  Google Scholar 

  6. Bäck M, Hlawaty H, Labat C, et al.: The oral cavity and age: a site of chronic inflammation. PLoS ONE 2007, 2:e1351.

    Article  PubMed  CAS  Google Scholar 

  7. Gaber F, James A, Delin I et al.: Assessment of in vivo 5-lipoxygenase activity by analysis of leukotriene B4 in saliva: effects of treatment with zileuton. J Allergy Clin Immunol 2007, 119:1267–1268.

    Article  PubMed  CAS  Google Scholar 

  8. Bäck M, Airila-Månsson S, Jogestrand T, et al.: Increased leukotriene concentrations in gingival crevicular fluid from subjects with periodontal disease and atherosclerosis. Atherosclerosis 2007, 193:389–394.

    Article  PubMed  CAS  Google Scholar 

  9. Dwyer JH, Allayee H, Dwyer KM, et al.: Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis. N Engl J Med 2004, 350:29–37.

    Article  PubMed  CAS  Google Scholar 

  10. Helgadottir A, Manolescu A, Helgason A, et al.: A variant of the gene encoding leukotriene A4 hydrolase confers ethnicity-specific risk of myocardial infarction. Nat Genet 2006, 38:68–74.

    Article  PubMed  CAS  Google Scholar 

  11. Freiberg JJ, Tybjaerg-Hansen A, Sillesen H, et al.: Promotor polymorphisms in leukotriene C4 synthase and risk of ischemic cerebrovascular disease. Arterioscler Thromb Vasc Biol 2008 (in press).

  12. Maznyczka A, Mangino M, Whittaker A, et al.: 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 (Lond) 2007, 112:411–416.

    Article  CAS  Google Scholar 

  13. Bäck M: Leukotriene receptors: crucial components in vascular inflammation. Scientific World Journal 2007, 7:1422–1439.

    PubMed  Google Scholar 

  14. Bäck M, Norel X, Walch L, et al.: Prostacyclin modulation of contractions of the human pulmonary artery by cysteinyl-leukotrienes. Eur J Pharmacol 2000, 401:389–395.

    Article  PubMed  Google Scholar 

  15. Ciana P, Fumagalli M, Trincavelli ML, et al.: The orphan receptor GPR17 identified as a new dual uracil nucleotides/cysteinyl-leukotrienes receptor. EMBO J 2006, 25:4615–4627.

    Article  PubMed  CAS  Google Scholar 

  16. Bäck M, Bu DX, Bränstrom R, et al.: Leukotriene B4 signaling through NF-kappaB-dependent BLT1 receptors on vascular smooth muscle cells in atherosclerosis and intimal hyperplasia. Proc Natl Acad Sci U S A 2005, 102:17501–17506.

    Article  PubMed  CAS  Google Scholar 

  17. Kim N, Luster AD: Regulation of immune cells by eicosanoid receptors. Scientific World Journal 2007, 7:1307–1328.

    PubMed  CAS  Google Scholar 

  18. Subbarao K, Jala VR, Mathis S, et al.: Role of leukotriene B4 receptors in the development of atherosclerosis: potential mechanisms. Arterioscler Thromb Vasc Biol 2004, 24:369–375.

    Article  PubMed  CAS  Google Scholar 

  19. Zhao L, Moos MP, Grabner R, et al.: The 5-lipoxygenase pathway promotes pathogenesis of hyperlipidemia-dependent aortic aneurysm. Nat Med 2004, 10:966–973.

    Article  PubMed  CAS  Google Scholar 

  20. Robertson AK, Rudling M, Zhou X, et al.: Disruption of TGF-beta signaling in T cells accelerates atherosclerosis. J Clin Invest 2003, 112:1342–1350.

    PubMed  CAS  Google Scholar 

  21. Bäck M, Sultan A, Ovchinnikova O, Hansson GK: 5-Lipoxygenase-activating protein: a potential link between innate and adaptive immunity in atherosclerosis and adipose tissue inflammation. Circ Res 2007, 100:946–949.

    Article  PubMed  CAS  Google Scholar 

  22. Ring WL, Riddick CA, Baker JR, et al.: Lymphocytes stimulate expression of 5-lipoxygenase and its activating protein in monocytes in vitro via granulocyte macrophage colony-stimulating factor and interleukin 3. J Clin Invest 1996, 97:1293–1301.

    Article  PubMed  CAS  Google Scholar 

  23. Aiello RJ, Bourassa PA, Lindsey S, et al.: Leukotriene B4 receptor antagonism reduces monocytic foam cells in mice. Arterioscler Thromb Vasc Biol 2002, 22:443–449.

    Article  PubMed  CAS  Google Scholar 

  24. Bäck M, Hansson GK: Leukotriene receptors in atherosclerosis. Ann Med 2006, 38:493–502.

    Article  PubMed  CAS  Google Scholar 

  25. Mita H, Hasegawa M, Saito H, Akiyama K: Levels of cysteinyl leukotriene receptor mRNA in human peripheral leucocytes: significantly higher expression of cysteinyl leukotriene receptor 2 mRNA in eosinophils. Clin Exp Allergy 2001, 31:1714–1723.

    Article  PubMed  CAS  Google Scholar 

  26. Gronert K, Martinsson-Niskanen T, Ravasi S, et al.: Selectivity of recombinant human leukotriene D4, leukotriene B4, and lipoxin A4 receptors with aspirin-triggered 15-epi-LXA(4) and regulation of vascular and inflammatory responses. Am J Pathol 2001, 158:3–9.

    PubMed  CAS  Google Scholar 

  27. Bäck M, Qiu H, Haeggstrom JZ, Sakata K: Leukotriene B4 is an indirectly acting vasoconstrictor in guinea pig aorta via an inducible type of BLT receptor. Am J Physiol Heart Circ Physiol 2004, 287:H419–H424.

    Article  PubMed  Google Scholar 

  28. Sakata K, Dahlén SE, Bäck M: The contractile action of leukotriene B4 in the guinea-pig lung involves a vascular component. Br J Pharmacol 2004, 141:449–456.

    Article  PubMed  CAS  Google Scholar 

  29. Heller EA, Liu E, Tager AM, et al.: Inhibition of atherogenesis in BLT1-deficient mice reveals a role for LTB4 and BLT1 in smooth muscle cell recruitment. Circulation 2005, 112:578–586.

    Article  PubMed  Google Scholar 

  30. Kondo K, Umemura K, Ohmura T, et al.: Suppression of intimal hyperplasia by a 5-lipoxygenase inhibitor, MK-886: studies with a photochemical model of endothelial injury. Thromb Haemost 1998, 79:635–639.

    PubMed  CAS  Google Scholar 

  31. Cipollone F, Mezzetti A, Fazia ML, et al.: Association between 5-lipoxygenase expression and plaque instability in humans. Arterioscler Thromb Vasc Biol 2005, 25:1665–1670.

    Article  PubMed  CAS  Google Scholar 

  32. Qiu H, Gabrielsen A, Agardh HE, et al.: Expression of 5-lipoxygenase and leukotriene A4 hydrolase in human atherosclerotic lesions correlates with symptoms of plaque instability. Proc Natl Acad Sci U S A 2006, 103:8161–8166.

    Article  PubMed  CAS  Google Scholar 

  33. Newby AC: Dual role of matrix metalloproteinases (matrixins) in intimal thickening and atherosclerotic plaque rupture. Physiol Rev 2005, 85:1–31.

    Article  PubMed  CAS  Google Scholar 

  34. Leppert D, Hauser SL, Kishiyama JL, et al.: Stimulation of matrix metalloproteinase-dependent migration of T cells by eicosanoids. FASEB J 1995, 9:1473–1481.

    PubMed  CAS  Google Scholar 

  35. Ichiyama T, Kajimoto M, Hasegawa M, et al.: Cysteinyl leukotrienes enhance tumour necrosis factor-alpha-induced matrix metalloproteinase-9 in human monocytes/macrophages. Clin Exp Allergy 2007, 37:608–614.

    Article  PubMed  CAS  Google Scholar 

  36. Ahluwalia N, Lin AY, Tager AM, et al.: Inhibited aortic aneurysm formation in BLT1-deficient mice. J Immunol 2007, 179:691–697.

    PubMed  CAS  Google Scholar 

  37. Mehrabian M, Allayee H, Wong J, et al.: Identification of 5-lipoxygenase as a major gene contributing to atherosclerosis susceptibility in mice. Circ Res 2002, 91:120–126.

    Article  PubMed  CAS  Google Scholar 

  38. Cao RY, Adams MA, Habenicht AJ, Funk CD: Angiotensin II-induced abdominal aortic aneurysm occurs independently of the 5-lipoxygenase pathway in apolipoprotein E-deficient mice. Prostaglandins Other Lipid Mediat 2007, 84:34–42.

    Article  PubMed  CAS  Google Scholar 

  39. Ghazalpour A, Wang X, Lusis AJ, Mehrabian M: Complex inheritance of the 5-lipoxygenase locus influencing atherosclerosis in mice. Genetics 2006, 173:943–951.

    Article  PubMed  CAS  Google Scholar 

  40. Jawien J, Gajda M, Rudling M, et al.: Inhibition of five lipoxygenase activating protein (FLAP) by MK-886 decreases atherosclerosis in apoE/LDLR-double knockout mice. Eur J Clin Invest 2006, 36:141–146.

    Article  PubMed  CAS  Google Scholar 

  41. Jawien J, Gajda M, Olszanecki R, Korbut R: BAY × 1005 attenuates atherosclerosis in apoE/LDLR — double knockout mice. J Physiol Pharmacol 2007, 58:583–588.

    PubMed  CAS  Google Scholar 

  42. Kaetsu Y, Yamamoto Y, Sugihara S, et al.: Role of cysteinyl leukotrienes in the proliferation and the migration of murine vascular smooth muscle cells in vivo and in vitro. Cardiovasc Res 2007, 76:160–166.

    Article  PubMed  CAS  Google Scholar 

  43. Porreca E, Di Febbo C, Di Sciullo A, et al.: Cysteinyl leukotriene D4 induced vascular smooth muscle cell proliferation: a possible role in myointimal hyperplasia. Thromb Haemost 1996, 76:99–104.

    PubMed  CAS  Google Scholar 

  44. Patrignani P, Daffonchio L, Hernandez A, et al.: Release of contracting autacoids by aortae of normal and atherosclerotic rabbits. J Cardiovasc Pharmacol 1992, 20(Suppl 12):S208–S210.

    PubMed  CAS  Google Scholar 

  45. Sala A, Rossoni G, Berti F, et al.: Monoclonal anti-CD18 antibody prevents transcellular biosynthesis of cysteinyl leukotrienes in vitro and in vivo and protects against leukotriene-dependent increase in coronary vascular resistance and myocardial stiffness. Circulation 2000, 101:1436–1440.

    PubMed  CAS  Google Scholar 

  46. Vidal C, Gomez-Hernandez A, Sanchez-Galan E, et al.: Licofelone, a balanced inhibitor of cyclooxygenase and 5-lipoxygenase, reduces inflammation in a rabbit model of atherosclerosis. J Pharmacol Exp Ther 2007, 320:108–116.

    Article  PubMed  CAS  Google Scholar 

  47. Hakonarson H, Thorvaldsson S, Helgadottir A, et al.: Effects of a 5-lipoxygenase-activating protein inhibitor on biomarkers associated with risk of myocardial infarction: a randomized trial. JAMA 2005, 293:2245–2256.

    Article  PubMed  CAS  Google Scholar 

  48. Whatling C, McPheat W, Herslöf M: The potential link between atherosclerosis and the 5-lipoxygenase pathway: investigational agents with new implications for the cardiovascular field. Expert Opin Investig Drugs 2007, 16:1879–1893.

    Article  PubMed  CAS  Google Scholar 

  49. Allayee H, Hartiala J, Lee W, et al.: The effect of montelukast and low-dose theophylline on cardiovascular disease risk factors in asthmatics. Chest 2007, 132:868–874.

    Article  PubMed  CAS  Google Scholar 

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Bäck, M. Inflammatory signaling through leukotriene receptors in atherosclerosis. Curr Atheroscler Rep 10, 244–251 (2008). https://doi.org/10.1007/s11883-008-0038-7

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