PPARα activators inhibit tissue factor expression and activity in human monocytes

• Published in: Circulation (New York, N.Y.) Vol. 103; no. 2; pp. 213 - 219
• Main Authors: MARX, Nikolaus, MACKMAN, Nigel, SCHÖNBECK, Uwe, YILMAZ, Nurcan, HOMBACH, Vinzenz, LIBBY, Peter, PLUTZKY, Jorge
• Format: Conference Proceeding Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 16.01.2001
• Subjects: Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Medical sciences; Vascular disease; Human; Cell culture; Monocyte; Pathogenesis; Atherosclerosis; Tissue factor; Cardiovascular disease; Thrombosis; Peroxisome proliferator; Biological receptor
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.103.2.213

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-α (PPARα), 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 PPARα activators limit TF responses in human monocytic cells. Methods and Results —Pretreatment of freshly isolated human monocytes or monocyte-derived macrophages with PPARα 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 PPARγ activators (15-deoxy _Δ12,14 -prostaglandin J 2 and BRL49653 ) lacked similar effects. WY14643 also decreased tumor necrosis factor-α 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-κB but not to be due to reduced nuclear factor-κB binding. Conclusions —PPARα 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 PPARα-activating fibric acid derivatives and certain fatty acids might influence atherothrombosis in patients with vascular disease.