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-1beta and TNF-alpha). 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 micromol/L) reduced EP-1/-3/-4 expression, along with COX-2, mPGES-1, MMP-9, and
PGE2 levels elicited by IL-1beta and
TNF-alpha. Similar results were noted with
aspirin (100 micromol/L),
dexamethasone (1 micromol/L), and the
Rho kinase inhibitors
Y-27632 and
fasudil (10 micromol/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.