The potential link between atherosclerosis and the 5-lipoxygenase pathway: investigational agents with new implications for the cardiovascular field.
The 5-lipoxygenase pathway is responsible for the production of leukotrienes--inflammatory lipid mediators that have a role in innate immunity, but that can also have pathological effects in inflammatory diseases. Recently, a potential link between leukotriene production and atherosclerosis has been proposed. The expression of leukotriene biosynthetic enzymes and leukotriene receptors has been identified in coronary and carotid atherosclerotic plaques, and the levels of biosynthetic enzymes have been correlated with the clinical symptoms of unstable plaques. Genetic variants in 5-lipoxygenase pathway genes have also been associated with a relative risk of developing myocardial infarction and stroke. On the basis of these discoveries, antileukotriene compounds are now being evaluated for the treatment of cardiovascular disease. Several tool compounds have been shown to limit the progression of lesion development in preclinical models of atherosclerosis, and three compounds, including two drugs previously developed for asthma, are undergoing clinical trials in patients with acute coronary syndromes.
Whatling
Carl
C
AstraZeneca R&D Mölndal, Bioscience Department, Pepparedsleden 1, 431 83 Mölndal, Sweden. carl.whatling@astrazeneca.com
McPheat
William
W
Herslöf
Margareta
M
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D050197:Atherosclerosis / Q000188:drug therapy / Q000201:enzymology*; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000201:enzymology; D002986:Clinical Trials as Topic; D015507:Drugs, Investigational / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D016859:Lipoxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
D015507:Drugs, Investigational; D016859:Lipoxygenase Inhibitors; D001094:Arachidonate 5-Lipoxygenase