Inhibitors of the 5-lipoxygenase pathway in atherosclerosis.
The inflammatory environment within the atherosclerotic lesion stimulates the 5-lipoxygenase pathway of arachidonic acid metabolism, leading to the biosynthesis of the potent lipid inflammatory mediators leukotrienes. The present review summarizes the components of this pathway; the enzymes 5-lipoxygenase (5-LO, ALOX5) with its activating protein, FLAP (ALOX5AP), LTA(4) hydrolase and LTC(4) synthase, as well as the receptors for leukotriene B(4) (BLT(1) and BLT(2)) and cysteinyl-leukotrienes (CysLT(1) and CysLT(2)), respectively. Genetic variations within the genes encoding these proteins have been associated with cardiovascular risk. Inhibiting the 5-lipoxygenase pathway through either leukotriene synthesis inhibitors or leukotriene receptor antagonists in experimental models of atherosclerosis has however generated contradictory results. Several inhibitors of the 5-lipoxygenase pathway are now evaluated in clinical trials of patients with cardiovascular disease.
Bäck
Magnus
M
Department of Cardiology and Center for Molecular Medicine, Karolinska University Hospital, 17176 Stockholm, Sweden. Magnus.Back@ki.se
D058927:5-Lipoxygenase-Activating Proteins; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D015195:Drug Design; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007249:Inflammation / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D020024:Leukotriene Antagonists / Q000627:therapeutic use; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D018077:Receptors, Leukotriene / Q000187:drug effects / Q000378:metabolism; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D016896:Treatment Outcome
D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; D000893:Anti-Inflammatory Agents; D002352:Carrier Proteins; D000960:Hypolipidemic Agents; D020024:Leukotriene Antagonists; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D018077:Receptors, Leukotriene; D018102:Receptors, Leukotriene B4; C412375:cysteinyl leukotriene receptor 2; D001094:Arachidonate 5-Lipoxygenase; D005982:Glutathione Transferase; D004851:Epoxide Hydrolases; C041116:leukotriene-C4 synthase; C083169:leukotriene D4 receptor; C043134:leukotriene A4 hydrolase