BACKGROUND AND OBJECTIVE: Prostaglandin E2 (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 PGE2 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-kappaB) 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). PGE2 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-kappaB and COX-2, mPGES-1 and EPs proteins were colocalized in the plaque's cells. In cytokine-treated cultured THP-1, the NF-kappaB inhibitors parthenolide, Bay 11-7082 and PDTC reduced COX-2, mPGES-1 and EP-1/EP-3/EP-4 expression as well as PGE2 levels. By employing specific agonists and antagonists, we noted that the cytokine- and PGE2-induced metalloproteinase 9 (MMP-9) expression and activity occurs through EP-1/EP-3/EP-4, an effect downregulated by NF-kappaB 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-kappaB inhibitors and/or EPs antagonists could represent a novel therapeutic approach to the treatment of plaque instability and rupture.
BACKGROUND AND OBJECTIVE:Prostaglandin E2 (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 PGE2 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-kappaB) 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). PGE2 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-kappaB and COX-2, mPGES-1 and EPs proteins were colocalized in the plaque's cells. In cytokine-treated cultured THP-1, the NF-kappaB inhibitors parthenolide, Bay 11-7082 and PDTC reduced COX-2, mPGES-1 and EP-1/EP-3/EP-4 expression as well as PGE2 levels. By employing specific agonists and antagonists, we noted that the cytokine- and PGE2-induced metalloproteinase 9 (MMP-9) expression and activity occurs through EP-1/EP-3/EP-4, an effect downregulated by NF-kappaB 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-kappaB inhibitors and/or EPs antagonists could represent a novel therapeutic approach to the treatment of plaque instability and rupture.
Authors: Rozenn N Lemaitre; Kenneth Rice; Kristin Marciante; Joshua C Bis; Thomas S Lumley; Kerri L Wiggins; Nicholas L Smith; Susan R Heckbert; Bruce M Psaty Journal: Atherosclerosis Date: 2008-11-01 Impact factor: 5.162
Authors: Vladimir R Babaev; Joshua D Chew; Lei Ding; Sarah Davis; Matthew D Breyer; Richard M Breyer; John A Oates; Sergio Fazio; Macrae F Linton Journal: Cell Metab Date: 2008-12 Impact factor: 27.287
Authors: G Herrero-Beaumont; M E Marcos; O Sánchez-Pernaute; R Granados; L Ortega; E Montell; J Vergés; J Egido; R Largo Journal: Br J Pharmacol Date: 2008-04-21 Impact factor: 8.739