Paraoxonase 1 hydrolysis of EPA-derived lactone impairs endothelial-mediated vasodilation

Human serum paraoxonase-1 (PON1) is a lactonase that plays a significant role in anti-atherosclerotic high-density lipoprotein (HDL) activity. PON1 is also localized in endothelial cell membranes, where it is enzymatically active and regulates endothelial signals. PON1 has a high specificity for lipophilic lactones and has been shown to hydrolyze and regulate lactone lipid mediators derived from arachidonic polyunsaturated fatty acids (PUFA). Previously, we showed that an arachidonic acid lactone metabolite (AA-L) dose-dependently dilates PON1 gene deletion (PON1KO) mouse mesenteric arteries significantly more than wild-type arteries. In contrast, preincubation with HDL or rePON1 reduced AA-L-dependent vasodilation. Recently we showed that an additional 8-lactone metabolite derived from the eicosapentaenoic acid lactone, 5,6-8-DiHETE lactone (EPA-L) reduced blood pressure by dilating microvessels of hypertensive rats. However, whether PON1 regulates the activity of the EPA-L lipid mediator is unknown.