The current view on the role of leukotrienes in atherogenesis

Since inflammation plays an important role in atherogenesis, during recent years it has become apparent that the 5-lipoxygenase (5-LO) pathway may take significant part in modifying the pathogenesis of atherosclerosis. Indeed, it has been recently demonstrated that the 5-LO substantially contribute to atherosclerosis in both mouse models and humans. However, animal models potentially bear the risk of compensatory mechanisms, due to genetic modification of the target gene that render the results difficult to interpret. Another caveat is species differences between mice and humans. 5-LO expression in intimal atherosclerotic lesions varies between mice and humans; also, 5-LO and 12/15-LO appear to be differentially regulated in inflammatory cells of mice. Moreover, atherogenesis in mice differs in several facets from the human pathology. Thus, T cells, whose presence in all stages of atherosclerotic lesions is acknowledged, are underrepresented in murine models of atherosclerosis. 5-LO/LT pathway shows important disparities between murine and human atherosclerosis. Advanced human plaques show differences in 5-LO expression compared with mouse lesions. Taken together, in advanced human atherosclerosis, a role for 5-LO is likely, which is distinct from its role in early atherogenesis. This presence of the 5-LO/LT pathway in advanced lesions is not found in mouse models, which might be due to: (i) rapid progression of atheroma growth in mice vs. slower, often interrupted progression in humans; (ii) advanced human plaques display a higher degree of instability and risk to rupture than murine plaques; (iii) temporal dissociation in the Th1/Th2 'balance' at distinct lesion stages between mice and humans.