15-hydroxy-5-8-11-13-eicosatetraenoic-acid and Coronary-Artery-Disease

15(S)-Hydroxyeicosatetraenoic acid (15(S)-HETE), the major 15-lipoxygenase 1/2 (15-LO1/2) metabolite of arachidonic acid (AA), induces CD36 expression through xanthine oxidase and NADPH oxidase-dependent ROS production and Syk and Pyk2-dependent STAT1 activation. In line with these observations, 15(S)-HETE also induced foam cell formation involving ROS, Syk, Pyk2, and STAT1-mediated CD36 expression. In addition, peritoneal macrophages from Western diet-fed ApoE(-/-) mice exhibited elevated levels of xanthine oxidase and NADPH oxidase activities, ROS production, Syk, Pyk2, and STAT1 phosphorylation, and CD36 expression compared to those from ApoE(-/-):12/15-LO(-/-) mice and these events correlated with increased lipid deposits, macrophage content, and lesion progression in the aortic roots. Human atherosclerotic arteries also showed increased 15-LO1 expression, STAT1 phosphorylation, and CD36 levels as compared to normal arteries. Together, these findings suggest that 12/15-LO metabolites of AA, particularly 12/15(S)-HETE, might play a crucial role in atherogenesis by enhancing foam cell formation.

Topics: Animals; Apolipoproteins E; Arachidonate 12-Lipoxygenase; Arachidonate 15-Lipoxygenase; Blotting, Western; CD36 Antigens; Cells, Cultured; Chromatin Immunoprecipitation; Coronary Artery Disease; Electrophoretic Mobility Shift Assay; Foam Cells; Focal Adhesion Kinase 2; Hydroxyeicosatetraenoic Acids; Immunoprecipitation; Intracellular Signaling Peptides and Proteins; Lipids; Macrophages, Peritoneal; Male; Mice; Mice, Knockout; NADPH Oxidases; Phosphorylation; Promoter Regions, Genetic; Protein-Tyrosine Kinases; Reactive Oxygen Species; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; STAT1 Transcription Factor; Syk Kinase