Thiazolidinediones suppress endothelin-1 secretion from bovine vascular endothelial cells: a new possible role of PPARgamma on vascular endothelial function.

We examined the effect of troglitazone on immunoreactive endothelin-1 (ET-1) secretion from cultured bovine vascular endothelial cells (bVECs). Insulin (10(-9)-10(-7) M) stimulated ET-1 secretion in a dose-dependent fashion without any kinetic change. Troglitazone (1-20 microM) dose-dependently inhibited both spontaneous and insulin-stimulated ET-1 secretion. This inhibitory effect of troglitazone was associated with reduced ET-1 mRNA levels. Addition of indomethacin (100 microM) or Nw-nitro-l-arginine methyl ester (1 mM) and downregulation of protein kinase C by prolonged pretreatment of the cells with a phorbol ester, 12-O-tetradecanoylphorbol 13-acetate, did not affect the inhibitory effect of troglitazone at concentrations up to 10 microM. Troglitazone did not change the intracellular Ca2+ concentration stimulated by angiotensin II (10 microM). Other PPARgamma ligands, pioglitazone (1-10 microM) and 15-deoxy-delta 12, 14-prostaglandin J2 (1-10 microM), but not a PPARalpha ligand, bezafibrate (1-10 microM), dose-dependently suppressed spontaneous ET-1 secretion from bVECs. These results, taken together, suggest that troglitazone inhibits ET-1 mRNA expression and secretion in bVECs possibly through activation of PPARgamma. This inhibition may contribute to the hypotensive effect of troglitazone in insulin-resistant subjects.