Thiazolidinediones suppress endothelin-1 secretion from bovine vascular endothelial cells: A new possible role of PPAR gamma on vascular endothelial function

We examined the effect of troglitazone on immunoreactive endothelin-1 (ET-1 ) secretion from cultured bovine vascular endothelial cells (bVECs), Insuli n (10(-9)-10(-7) M) stimulated ET-1 secretion in a dose-dependent fashion w ithout any kinetic change, Troglitazone (1-20 mu M) dose-dependently inhibi ted both spontaneous and insulin-stimulated ET-1 secretion, This inhibitory effect of troglitazone was associated with reduced ET-1 mRNA levels. Addit ion of indomethacin (100 mu M) or Nw-nitro-L-arginine methyl ester (1 mM) a nd downregulation of protein kinase C by prolonged pretreatment of the cell s with a phorbol ester, 12-O-tetradecanoylphorbol 13-acetate, did not affec t the inhibitory effect of troglitazone at concentrations up to 10 mu M. Tr oglitazone did not change the intracellular Ca2+ concentration stimulated b y angiotensin II (10 mu M). Other PPAR gamma ligands, pioglitazone (1-10 mu M) and 15-deoxy-delta 12, 14-prostaglandin J(2) (1-10 mu M), but not a PPA R alpha ligand, bezafibrate (1-10 mu M), dose-dependently suppressed sponta neous ET-1 secretion from bVECs, These results, taken together, suggest tha t troglitazone inhibits ET-1 mRNA expression and secretion in bVECs possibl y through activation of PPAR gamma, This inhibition may contribute to the h ypotensive effect of troglitazone in insulin-resistant subjects. (C) 1999 A cademic Press.