(Circulation. 2001;103:213.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
PPAR
Activators Inhibit Tissue Factor Expression and Activity in Human Monocytes
From the Department of Internal Medicine II–Cardiology, University of Ulm (N. Marx, N.Y., V.H.), Ulm, Germany; the Departments of Immunology and Vascular Biology, The Scripps Research Institute (N. Mackman), La Jolla, Calif; and the Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School (U.S., P.L., J.P.), Boston, Mass.
Correspondence to Nikolaus Marx, MD, Department of Internal Medicine II, Cardiology, University of Ulm, Robert-Koch-Straße 8, D-89081 Ulm, Germany. E-mail nikolaus.marx{at}medizin.uni-ulm.de
Background—Tissue
factor (TF), expressed on the surface of monocytes and macrophages in
human atherosclerotic lesions, acts as the major procoagulant
initiating thrombus formation in acute coronary syndromes. Peroxisome
proliferator–activated receptor-
(PPAR), a nuclear receptor
family member, regulates gene expression in response to certain fatty
acids and fibric acid derivatives. Given that some of these substances
reduce TF activity in patients, we tested whether PPAR activators
limit TF responses in human monocytic
cells.
Methods and
Results—Pretreatment of freshly isolated human
monocytes or monocyte-derived macrophages with PPAR activators
WY14643 and eicosatetraynoic acid (ETYA) led to reduced
lipopolysaccharide (LPS)-induced TF activity in a
concentration-dependent manner (maximal reduction to 43±8% with 250
µmol/L WY14643 [P<0.05,
n=5] and to 42±12% with 30 µmol/L ETYA
[P>0.05, n=3]). Two
different PPAR
activators
(15-deoxy_
12,14-prostaglandin
J2 and BRL49653) lacked similar effects. WY14643
also decreased tumor necrosis factor- protein expression in
supernatants of LPS-stimulated human monocytes. Pretreatment of
monocytes with WY14643 inhibited LPS-induced TF protein and mRNA
expression without altering mRNA half-life. Transient transfection
assays of a human TF promoter construct in THP-1 cells revealed WY14643
inhibition of LPS-induced promoter activity, which appeared to be
mediated through the inhibition of nuclear factor-
B but not to be
due to reduced nuclear factor-B
binding.
Conclusions—PPAR
activators can reduce TF expression and activity in human
monocytes/macrophages and thus potentially reduce the thrombogenicity
of atherosclerotic lesions. These data provide new insight into how
PPAR-activating fibric acid derivatives and certain fatty acids
might influence atherothrombosis in patients with vascular
disease.
Key Words: leukocytes • thrombosis • genes • coagulation
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