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RESEARCH PRODUCT

Decreased Paraoxonase-2 Expression in Human Carotids During the Progression of Atherosclerosis

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Objective— Many gene products involved in oxidation and inflammation are implicated in the pathogenesis of atherosclerosis. We investigated paraoxonase 2 (PON2), 5-lipoxygenase (5-LO), and 5-LO activating protein (FLAP) expression and malondialdehyde (MDA) levels in carotid lesions to assess their involvement in plaque formation. Methods and Results— We measured gene expression and MDA levels in atherosclerotic plaques from 59 patients undergoing carotid endarterectomy, and in plaque-adjacent tissue from 41/59 patients. Twenty-three fetal carotids and 6 mammary arteries were also investigated. Real-time polymerase chain reaction and immunohistochemistry revealed decreased PON2 expression in plaques versus adjacent regions ( P <0.005, P <0.001, respectively), mammary arteries ( P <0.031, P <0.001, respectively), and fetal carotids (both P <0.001). mRNA levels of 5-LO and FLAP were higher ( P <0.038, P <0.005, respectively) in lesions versus fetal carotids. MDA was higher in plaques versus plaque-adjacent tissue and fetal carotids. PON2 mRNA was downregulated by oxidative stress in 5 ex vivo experiments, thereby indicating its possible atheroprotection role. Conclusions— We demonstrate that PON2 mRNA and protein are decreased in plaques versus plaque-adjacent tissue, mammary arteries, and fetal carotids. Our data indicate that the protective effect of PON2 could fail during atherosclerosis exacerbation; this was confirmed by the increase of MDA levels. The increase of 5-LO and FLAP mRNA expression confirms their role as inflammatory markers associated to atherosclerosis.