Saturated fatty acids increase peroxynitrite formation via a SR‐BI/caveolin/AMP kinase signaling pathway

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The goal of these studies was to determine the mechanism whereby saturated fatty acids increased peroxynitrite formation. Mouse aortic endothelial cells were treated with 10 μM of saturated or unsaturated fatty acids. Saturated fatty acids but not unsaturated fatty acids caused an increase in peroxynitrite. In contrast, saturated fatty acids did not increase peroxynitrite in aortic endothelial cells isolated from SR‐BI or caveolin‐1 null mice. To further explore the requirement of SR‐BI and caveolin‐1, aortic endothelial cells lacking these proteins were treated with adenovirus encoding either mouse SR‐BI or caveolin‐1. Expression of SR‐BI and caveolin‐1 restored the ability of saturated fatty acids to induce peroxynitrite formation. Bovine aortic endothelial cell lines that do not express AMP kinase or express AMP kinase from an adenoviral construct demonstrated that AMP kinase is also required for saturated fatty acids to induce peroxynitrite formation. Further studies demonstrated that saturated fatty acids induce the phosphorylation, and thus, activation of AMP kinase and nitric oxide synthase. Competition and binding assays demonstrated that saturated fatty acids directly bind to SR‐BI. Taken together these data suggest that binding of saturated fatty acids to SR‐BI initiates a signaling cascade that involves caveolin and AMP kinase which results in the production of peroxynitrite.