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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:594.)
© 2008 American Heart Association, Inc.

Clinical and Population Studies

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

Giuliana Fortunato; Maria Donata Di Taranto; Umberto Marcello Bracale; Luca Del Guercio; Francesca Carbone; Cristina Mazzaccara; Alberto Morgante; Francesco Paolo D’Armiento; Maria D’Armiento; Massimo Porcellini; Lucia Sacchetti; Giancarlo Bracale; Francesco Salvatore

From the Dipartimento di Biochimica e Biotecnologie Mediche (G.F., C.M., A.M., L.S., F.S.), Università degli Studi di Napoli "Federico II", Via S. Pansini 5, 80131 Napoli, Italy and CEINGE scarl, Via Comunale Margherita 482, 80145 Napoli, Italy; Dipartimento Assistenziale di Chirurgia Generale Toracica, Vascolare e Endovascolare (U.M.B., L.D.G., F.C., M.P., G.B.), Università degli Studi di Napoli "Federico II", Via S. Pansini 5, 80131 Napoli, Italy; Dipartimento di Scienze Biomorfologiche e Funzionali – Sezione Anatomia Patologica e Citopatologica (F.P.D., M.D.), Università degli Studi di Napoli "Federico II", Via S. Pansini 5, 80131 Napoli, Italy; IRCSS Fondazione SDN (M.D.D.T.), Via E. Gianturco 113, 80143 Napoli, Italy.

Correspondence to Prof Francesco Salvatore, Dipartimento di Biochimica e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II", Via S. Pansini 5, 80131 Napoli, Italy. E-mail salvator{at}unina.it

Abstract

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.

We measured the expression of the PON2, 5-LO, and FLAP genes in carotid atherosclerotic plaques. PON2 mRNA and protein progressively decreased with plaque severity, whereas 5LO and FLAP mRNA increased. We also show that oxidative stress downregulates PON2 mRNA expression, thus suggesting its role in atherosclerotic process.

Key Words: atherosclerosis • paraoxonase 2 (PON2) • carotid plaque • oxidative stress • fetal carotid and mammary artery