Overexpression of COX-2, Prostaglandin E Synthase-1 and Prostaglandin E Receptors in blood mononuclear cells and plaque of patients with carotid atherosclerosis:: Regulation by nuclear factor-κB

Background and objective: Prostaglandin E-2 (PGE(2)), a product of the cyclooxygenase 2 (COX-2) and membrane-associated Prostaglandin E Synthase (mPGES-1) pathway, has been implicated in the instability of atherosclerotic plaques. We have studied COX-2, mPGES-1 and PGE(2) receptors (EPs) expression in peripheral blood mononuclear cells (PBMC) and atherosclerotic plaques of 29 patients with carotid stenosis as well as the effect of different nuclear factor-kappaB (NF-kappa B) inhibitors on COX-2, mPGES-1 and EPs expression in cultured monocytic cells (THP-1). Methods: COX-2, mPGES-1 and EP expression was analyzed by RT-PCR (PBMC), immunohistochemistry (plaques) and Western blot (THP-1). PGE(2) levels were determined by ELISA (plasma and cell supernatants). Results: In relation to healthy controls, COX-2, mPGES-1 and EP-3/EP-4 mRNA expression was increased in PBMC from patients. In the inflammatory region of atherosclerotic plaques, an increase of COX-2, mPGES-1 and EPs expression was also observed. Activated NF-kappa B and COX-2. mPGES-1 and EPs proteins were colocalized in the plaque's cells. In cytokine-treated cultured THP-1, the NF-kappa B inhibitors parthenolide, Bay 11-7082 and PDTC reduced COX-2, mPGES-1 and EP-1/EP-3/EP-4 expression as well as PGE(2) levels. By employing specific agonists and antagonists, we noted that the cytokine- and PGE(2)-induced metalloproteinase 9 (NIMP-9) expression and activity occurs through EP-1/EP-3/EP-4, an effect downregulated by NF-kappa B inhibitors. Conclusions: Patients with carotid atherosclerosis depict an overexpression of COX-2, mPGES-1 and EPs simultaneously in the PBMC as well as in the vulnerable region of plaques. The studies in cultured monocytic cells suggest that NF-kappa B inhibitors and/or EPs antagonists could represent a novel therapeutic approach to the treatment of plaque instability and rupture. (c) 2005 Elsevier Ireland Ltd. All rights reserved.