Synthetic peroxisome proliferator-activated receptor γ agonists rosiglitazone and troglitazone suppress transcription by promoter 3 of the human thromboxane A2 receptor gene in human erythroleukemia cells

The human thromboxane (TX)A2 receptor (TP) gene encodes two TP isoforms, TPα and TPβ, that are regulated by distinct promoters designated promoter Prm1 and Prm3, respectively. Previous studies established that 15d-Δ12,14-prostaglandin J2 (15d-PGJ2) selectively inhibits Prm3 activity and TPβ expression through a peroxisome proliferator-activated receptor (PPAR)γ mechanism without affecting Prm1 activity or TPα expression in human megakaryocytic erythroleukemia (HEL) 92.1.7 cells. Herein, we investigated the effect of synthetic thiazolidinedione (TZD) PPARγ ligands rosiglitazone and troglitazone on TP gene expression in HEL cells. Like 15d-PGJ2, both TZDs suppressed Prm3 activity, TPβ mRNA expression and TP-mediated calcium mobilization without affecting Prm1 or TPα mRNA expression. However, unlike 15d-PGJ2, both TZDs mediated their PPARγ-dependent effects through trans-repression of an activator protein-1 (AP-1) element, a site previously found to be critical for basal Prm3 activity. These data provide further evidence for the role of PPARγ in regulating the human TP gene; they highlight further differences in TPα and TPβ expression/regulation and point to essential differences between natural and synthetic PPARγ agonists in mediating those effects.