Paraoxonase-1 deficiency in mice predisposes to vascular inflammation, oxidative stress, and thrombogenicity in the absence of hyperlipidemia
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BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: Our data revealed significant vascular changes in adhesion, oxidative stress, and thrombotic tendencies in Pon1(-/-) mice in the absence of hyperlipidemia and systemic inflammation.
