Paraoxonase-1 deficiency in mice predisposes to vascular inflammation, oxidative stress, and thrombogenicity in the absence of hyperlipidemia

Abstract

Paraoxonase-1 is a polymorphic enzyme that is strongly associated with circulating high-density lipoproteins. The absence of paraoxonase-1 in mice has been shown to promote diet-induced atherosclerosis. As paraoxonase-1 has been recently shown to be a lactonase, its functional role remains to be fully elucidated. We explored additional vascular changes in Pon1 knockout mice in the absence of atherogenic diet challenge. Early steps in atherogenesis, namely, leukocyte rolling and firm adhesion, were measured using intravital microscopy. Vascular oxidative status was determined by lucigenin-derived chemiluminescence. Arterial thrombosis was determined by in vivo carotid thrombosis assay. Gene expressions were determined by reverse transcription polymerase chain reaction. We observed a twofold increase in leukocyte adhesion, but no significant change in leukocyte rolling in Pon1(-/-) mice versus wild-type controls. This finding is correlated with a 1.6-fold increase in aortic mRNA levels of P-selectin (P<.016), a 1.3-fold up-regulation in Vcam1 (P=.096), and a 1.5-fold up-regulation in Icam1 (P=.016). Aortic Tnfalpha mRNA expression was unchanged. Pon1(-/-) mice were also found to show a threefold increase in aortic superoxide production rate (P=.04). Furthermore, carotid thrombosis assay revealed a 57% reduction in time to occlusion in Pon1(-/-) mice (P<.001). In spite of such vascular proinflammatory phenotypes, we observed no change in plasma levels of inflammatory cytokines or in hepatic mRNA expression of serum amyloid A. Our data revealed significant vascular changes in adhesion, oxidative stress, and thrombotic tendencies in Pon1(-/-) mice in the absence of hyperlipidemia and systemic inflammation.