The Paraoxonase Gene Cluster Protects Against Abdominal Aortic Aneurysm Formation

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Abstract

Objective—

Abdominal aortic aneurysm (AAA) is a life-threatening vascular pathology, the pathogenesis of which is closely related to oxidative stress. However, an effective pharmaceutical treatment is lacking because the exact cause of AAA remains unknown. Here, we aimed at delineating the role of the paraoxonases (PONs) gene cluster (PC), which prevents atherosclerosis through the detoxification of oxidized substrates, in AAA formation.

Approach and Results—

PC transgenic (Tg) mice were crossed to an Apoe−/− background, and an angiotensin II–induced AAA mouse model was used to analyze the effect of the PC on AAA formation. Four weeks after angiotensin II infusion, PC-Tg Apoe−/− mice had a lower AAA incidence, smaller maximal abdominal aortic external diameter, and less medial elastin degradation than Apoe−/− mice. Importantly, PC-Tg Apoe−/− mice exhibited lower aortic reactive oxidative species production and oxidative stress than did the Apoe−/− control mice. As a consequence, the PC transgene alleviated angiotensin II–induced arterial inflammation and suppressed arterial extracellular matrix degradation. Specifically, on angiotensin II stimulation, PC-Tg vascular smooth muscle cells exhibited lower levels of reactive oxidative species production and a decrease in the activities and expression levels of matrix metalloproteinase-2 and matrix metalloproteinase-9. Moreover, PC-Tg serum also enhanced vascular smooth muscle cell oxidative stress resistance and further decreased the expression levels of matrix metalloproteinase-2 and matrix metalloproteinase-9, indicating that circulatory and vascular smooth muscle cell PC members suppress oxidative stress in a synergistic manner.

Conclusions—

Our findings reveal, for the first time, a protective role of the PC in AAA formation and suggest PONs as promising targets for AAA prevention.

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