Atorvastatin reduces the expression of prostaglandin E2 receptors in human carotid atherosclerotic plaques and monocytic cells: Potential implications for plaque stabilization

Prostaglandin E2 (PGE2), the product of cyclooxygenase-2 (COX-2) and prostaglandin E synthase-1 (mPGES-1), acts through its receptors (EPs) and induces matrix metalloproteinase (MMP) expression, which may favor the instability of atherosclerotic plaques. The effect of statins on EPs expression has not been previously studied. The aim of this study was to investigate the effect of atorvastatin (ATV, 80 mg/d, for one month) on EP expression in plaques and peripheral blood mononuclear cells (PBMC) of patients with carotid atherosclerosis. In addition, we studied the mechanisms by which statins could modulate EPs expression on cultured monocytic cells (THP-1) stimulated with proinflammatory cytokines (IL-1β and TNF-α). Patients treated with atorvastatin showed reduced EP-1 (14 ± 1.8% versus 26 ± 2%; P < 0.01), EP-3 (10 ± 1.5% versus 26 ± 1.5%; P < 0.05), and EP-4 expression (10 ± 4.1% versus 26.6 ± 4.9%; P < 0.05) in atherosclerotic plaques (immunohistochemistry), and EP-3 and EP-4 mRNA expression in PBMC (real time PCR) in relation to non-treated patients. In cultured monocytic cells, atorvastatin (10 μmol/L) reduced EP-1/-3/-4 expression, along with COX-2, mPGES-1, MMP-9, and PGE2 levels elicited by IL-1β and TNF-α. Similar results were noted with aspirin (100 μmol/L), dexamethasone (1 μmol/L), and the Rho kinase inhibitors Y-27632 and fasudil (10 μmol/L both). The effect of atorvastatin was reversed by mevalonate, farnesyl pyrophosphate, and geranylgeranyl pyrophosphate. On the whole, we have shown that atorvastatin reduces EPs expression in atherosclerotic plaques and blood mononuclear cells of patients with carotid stenosis and in cultured monocytic cells. The inhibition of EP receptors could explain, at least in part, some of the mechanisms by which statins could modulate the COX-2/mPGES-1 proinflammatory pathway and favor plaque stabilization in humans.