PPARalpha agonists inhibit tissue factor expression in human monocytes and macrophages

Monocytic tissue factor (TF) expression may contribute to thrombogenicity associated with plaque rupture and may propagate thrombus formation at the site of vascular lesions. Induction of monocytic TF expression by endotoxin is mediated by the activation of transcription factors such as AP-1 and NF-kappaB. Both these signaling pathways are modulated by peroxisome proliferator-activated receptor-alpha (PPARalpha). Therefore, we have studied the effects of fibrates and other PPARalpha agonists on the expression of TF.

We show that PPARalpha protein, like primary human monocytes, is also expressed in the human monocytic THP-1 cell line. Fenofibric acid, WY14643, and GW2331 inhibited TF mRNA upregulation after stimulation of THP-1 cells with lipopolysaccharide or interleukin-1ss. In primary human monocytes and macrophages, the lipopolysaccharide- or interleukin-1ss-mediated induction of TF activity was also inhibited by fenofibric acid, WY14643, or GW2331.

These data indicate that activation of PPARalpha results in the downregulation of the TF gene. Our results suggest a novel role for PPARalpha in the control of atherosclerotic plaque thrombogenicity through its effects on TF expression in monocytes and macrophages.