PPAR alpha agonists inhibit tissue factor expression in human monocytes and macrophages

Background-Monocytic tissue factor (TF) expression may contribute to thromb ogenicity associated with plaque rupture and may propagate thrombus formati on at the site of vascular lesions. Induction of monocytic TF expression by endotoxin is mediated by the activation of transcription factors such as A P-1 and NF-kappaB. Both these signaling pathways are modulated by peroxisom e proliferator-activated receptor-alpha (PPAR alpha). Therefore, we have st udied the effects of fibrates and other PPAR alpha agonists on the expressi on of TF. Methods and Results-We show that PPAR alpha protein, like primary human mon ocytes, is also expressed in the human monocytic THP-1 cell line. Fenofibri c acid,WY14643, and GW2331 inhibited TF mRNA upregulation after stimulation of THP-1cells with lipopolysaccharide or interleukin-1 beta. In primary hu man monocytes and macrophages, the lipopolysaccharide- or interleukin-1 bet a -mediated induction of TF activity was also inhibited by fenofibric acid, WY14643, or GW2331. Conclusions These data indicate that activation of PPARa results in the dow nregulation of the TF gene. Our results suggest a novel role fur PPAR alpha in the control of atherosclerotic plaque thrombogenicity through its effec ts on TF expression in monocytes and macrophages.