Nitric Oxide Production and Regulation of Endothelial Nitric-oxide Synthase Phosphorylation by Prolonged Treatment with Troglitazone
Nitric Oxide Production and Regulation of Endothelial Nitric-oxide Synthase Phosphorylation by Prolonged Treatment with Troglitazone
复制标题
曲格列酮长期治疗对一氧化氮的产生和内皮一氧化氮合酶磷酸化的调节
DOI：
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发表时间：
2004
影响因子：
4.8
通讯作者：
I. Jo
中科院分区：
文献类型：
--
作者：
D. Cho;Yoon Jung Choi;S. Jo;I. Jo
最近研究发现，过氧化物酶体增殖物激活受体γ(PPARγ)配体可增加内皮细胞NO含量，但其信号转导机制尚不清楚。以降糖药物曲格列酮为靶点，研究了曲格列酮对牛主动脉内皮细胞NO生成影响的分子机制。曲格列酮以剂量和时间依赖的方式增加内皮细胞NO的产生，但不改变内皮型一氧化氮合酶(ENOS)的表达。20μ间曲格列酮作用12h后，血管内皮细胞生长因子及其受体KdR/Flk-1的表达和Akt的磷酸化水平均升高，达最大值(KdR/Flk-1)。针对每个磷酸化位点的抗体分析表明，曲格列酮(20μm作用12h)显著增加eNOS Ser1179的磷酸化(eNOS-Ser1179)和eNOS-Ser116的去磷酸化，但不改变eNOS-Thr497的磷酸化。用抗血管内皮生长因子抗体清除曲格列酮增加的血管内皮生长因子，可部分抑制曲格列酮刺激的NO生成。同时，曲格列酮刺激的Akt和eNOS-Ser1179的磷酸化增加减弱，而eNOS-Ser116的去磷酸化没有变化。γ拮抗剂双酚A二缩水甘油醚可部分抑制曲格列酮刺激的NO生成，同时降低血管内皮生长因子受体/Flk-1-Akt介导的eNOS-Ser1179的磷酸化，但对曲格列酮诱导的eNOS-Ser116去磷酸化无影响。综上所述，我们的结果表明，长期使用曲格列酮至少通过两条独立的信号通路增加内皮细胞NO的产生：PPARγ依赖的、VEGFKDR/Flk-1-Akt介导的eNOS-Ser1179磷酸化和PPARγ非依赖的eNOS-Ser116去磷酸化。
Recently, peroxisome proliferator-activated receptor γ (PPARγ) ligands have been reported to increase endothelial NO, but the signaling mechanisms involved are unknown. Using troglitazone, a PPARγ ligand known as an antidiabetic compound, we investigated the molecular mechanism of its effect on NO production in bovine aortic endothelial cells. Troglitazone increased endothelial NO production in a dose- and time-dependent manner with no alteration in endothelial nitric-oxide synthase (eNOS) expression. The maximal increase (∼3.1-fold) was achieved with 20 μm troglitazone treatment for 12 h, and this increase was accompanied by increases in the expression of vascular endothelial growth factor (VEGF) and its receptor, KDR/Flk-1, and in Akt phosphorylation. Analysis with antibodies specific for each phosphorylated site demonstrated that troglitazone (20 μm treatment for 12 h) significantly increased both the phosphorylation of Ser1179 of eNOS (eNOS-Ser1179) and the dephosphorylation of eNOS-Ser116 but did not alter eNOS-Thr497 phosphorylation. Treatment with anti-VEGF antibody to scavenge the increased VEGF induced by troglitazone partially inhibited troglitazone-stimulated NO production. This was accompanied by the attenuation of troglitazone-stimulated increases in the phosphorylation of Akt and eNOS-Ser1179 with no alteration in eNOS-Ser116 dephosphorylation. We also found that bisphenol A diglycidyl ether, a PPARγ antagonist, partially inhibited troglitazone-stimulated NO production with a concomitant reduction in VEGF-KDR/Flk-1-Akt-mediated eNOS-Ser1179 phosphorylation but with no alteration in eNOS-Ser116 dephosphorylation induced by troglitazone. Taken together, our results demonstrate that prolonged treatment with troglitazone increases endothelial NO production by at least two independent signaling pathways: PPARγ-dependent, VEGF-KDR/Flk-1-Akt-mediated eNOS-Ser1179 phosphorylation and PPARγ-independent, eNOS-Ser116 dephosphorylation.
DOI：
10.1046/j.1365-201x.2000.00629.x
发表时间：
2000
期刊：
Acta physiologica Scandinavica
影响因子：
--
作者：
B. Kone
通讯作者：
B. Kone
吡格列酮对血管平滑肌钙通道的影响。
DOI：
10.1161/01.hyp.24.2.170
发表时间：
1994
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
--
作者：
Zhang,F;Sowers,JR;Ram,JL;Standley,PR;Peuler,JD
通讯作者：
Peuler,JD
影响因子：
158.5
作者：
NOLAN, JJ;LUDVIK, B;OLEFSKY, J
通讯作者：
OLEFSKY, J