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

Abstract

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 δ-lactone metabolite derived from the eicosapentaenoic acid lactone, 5,6-δ-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. AIM: To demonstrate that PON1 hydrolyzes EPA-L and to reveal the effect of this hydrolysis on endothelial-dependent vascular dilation.

METHODS AND RESULTS

In vascular reactivity experiments, EPA-L dose-dependently dilated PON1KO mouse mesenteric arteries significantly more than wild-type mesenteric arteries. This dilation was not affected by nitric oxide inhibition. PON1 impaired the cellular calcium increase mediated by EPA-L in endothelial cells, though this impairment decreased with PON1 internalization to the cell.

CONCLUSION

These findings support that PUFA-lactones are physiological substrates of PON1, and that PON1 activity in the endothelial membrane affects the dilation of microvessels that is induced by these endothelial-derived hyperpolarizing PUFA-lactones.