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Abstract
The enzyme 15-lipoxygenase (15-LO) plays a role in atherogenesis (also known as atherosclerosis), but the underlying mechanisms are unclear. We found that 15(S)-hydroxyeicosatetraenoic acid [15(S)-HETE], the major 15-LO–dependent metabolite of arachidonic acid, stimulated the production of reactive oxygen species (ROS) by monocytes through the xanthine oxidase–mediated activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. ROS production led to the Syk-, Pyk2-, and mitogen-activated protein kinase (MAPK)–dependent production of the proinflammatory cytokine interleukin-17A (IL-17A) in a manner that required the transcription factor CREB (cyclic adenosine monophosphate response element–binding protein). In addition, this pathway was required for the 15(S)-HETE–dependent migration and adhesion of monocytes to endothelial cells. Consistent with these observations, we found that peritoneal macrophages from apolipoprotein E–deficient (ApoE−/−) mice fed a high-fat diet (a mouse model of atherosclerosis) exhibited increased xanthine oxidase and NADPH oxidase activities; ROS production; phosphorylation of Syk, Pyk2, MAPK, and CREB; and IL-17A production compared to those from similarly fed ApoE−/−:12/15-LO−/− mice. These events correlated with increased lipid deposits and numbers of monocytes and macrophages in the aortic arches of ApoE−/− mice, which resulted in atherosclerotic plaque formation. Together, these observations suggest that 15(S)-HETE exacerbates atherogenesis by enhancing CREB-dependent IL-17A production and inflammation.
