Satoh H, Tsukamoto K, Hashimoto Y, Hashimoto N, Togo M, Hara M, Maekawa H, Isoo N, Kimura S, Watanabe T
First Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, 113-0033, USA.
Biochem Biophys Res Commun. 1999 Jan 27;254(3):757-63. doi: 10.1006/bbrc.1998.0126.
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.
我们研究了曲格列酮对培养的牛血管内皮细胞（bVECs）中免疫反应性内皮素-1（ET-1）分泌的影响。胰岛素（10^(-9)-10^(-7) M）以剂量依赖性方式刺激ET-1分泌，且无任何动力学变化。曲格列酮（1-20 microM）剂量依赖性地抑制自发和胰岛素刺激的ET-1分泌。曲格列酮的这种抑制作用与ET-1 mRNA水平降低有关。添加吲哚美辛（100 microM）或Nω-硝基-L-精氨酸甲酯（1 mM），以及用佛波酯12-O-十四酰佛波醇13-乙酸酯对细胞进行长时间预处理下调蛋白激酶C，在浓度高达10 microM时均不影响曲格列酮的抑制作用。曲格列酮不改变血管紧张素II（10 microM）刺激的细胞内Ca2+浓度。其他过氧化物酶体增殖物激活受体γ（PPARγ）配体，吡格列酮（1-10 microM）和15-脱氧-Δ12,14-前列腺素J2（1-10 microM），但不是过氧化物酶体增殖物激活受体α（PPARα）配体苯扎贝特（1-10 microM），剂量依赖性地抑制bVECs的自发ET-1分泌。综上所述，这些结果表明曲格列酮可能通过激活PPARγ抑制bVECs中ET-1 mRNA的表达和分泌。这种抑制作用可能有助于曲格列酮对胰岛素抵抗受试者的降压作用。
