Ghrelin has novel vascular actions that mimic PI 3-kinase-dependent actions of insulin to stimulate production of NO from endothelial cells
Ghrelin has novel vascular actions that mimic PI 3-kinase-dependent actions of insulin to stimulate production of NO from endothelial cells
复制标题
DOI：
10.1152/ajpendo.00570.2006
复制
发表时间：
2007-03-01
影响因子：
5.1
通讯作者：
Quon, Michael J.
中科院分区：
文献类型：
--
作者：
Iantorno, Micaela;Chen, Hui;Quon, Michael J.
Ghrelin是一种由胃分泌的促食欲肽激素。在患有代谢综合征和低ghrelin水平的患者中，动脉内给予ghrelin可急性改善其内皮功能障碍。因此，我们假设生长素释放肽激活血管内皮中的内皮型一氧化氮合酶（eNOS），从而使用与胰岛素受体共有的信号通路增加一氧化氮（NO）的产生。与胰岛素类似，生长素释放肽以时间和剂量依赖性方式急性刺激原代培养的牛主动脉内皮细胞（BAEC）中NO的产生增加（使用NO特异性荧光染料4，5-二氨基荧光素评估）。响应于ghrelin的NO的产生用N-G-硝基-L-精氨酸甲酯预处理细胞，（一氧化氮合酶抑制剂）、渥曼青霉素[磷脂酰肌醇（PI）3-激酶抑制剂]或（D-Lys（3））-GHRP-6（生长素释放肽受体GHSR-1a的选择性拮抗剂），以及通过使用小干扰（si）RNA敲低GHSR-1a（但不是通过促分裂原/细胞外信号调节激酶抑制剂PD-98059）。此外，ghrelin刺激Akt（Ser（473））和eNOS（Akt磷酸化位点Ser（1179））的磷酸化增加，这可通过使用siRNA敲低GHSR-1a或通过用渥曼青霉素预处理细胞而不是用PD-98059预处理细胞来实现。Ghrelin还刺激BAEC中促分裂原活化蛋白（MAP）激酶的磷酸化。然而，与胰岛素不同，ghrelin并不刺激BAEC依赖MAP激酶的血管收缩剂内皮素-1的分泌。我们的结论是，生长激素释放肽有新的血管行动，急性刺激生产的NO在内皮细胞使用的信号通路，涉及GHSR-1a，PI 3-激酶，Akt，和eNOS。我们的研究结果可能与开发新的治疗策略，以治疗糖尿病和相关疾病的特点是内皮功能障碍和胰岛素抵抗之间的相互关系。
Ghrelin is an orexigenic peptide hormone secreted by the stomach. In patients with metabolic syndrome and low ghrelin levels, intra-arterial ghrelin administration acutely improves their endothelial dysfunction. Therefore, we hypothesized that ghrelin activates endothelial nitric oxide synthase ( eNOS) in vascular endothelium, resulting in increased production of nitric oxide ( NO) using signaling pathways shared in common with the insulin receptor. Similar to insulin, ghrelin acutely stimulated increased production of NO in bovine aortic endothelial cells ( BAEC) in primary culture ( assessed using NO-specific fluorescent dye 4,5-diaminofluorescein) in a time-and dose-dependent manner. Production of NO in response to ghrelin ( 100 nM, 10 min) in human aortic endothelial cells was blocked by pretreatment of cells with N-G-nitro-L-arginine methyl ester ( nitric oxide synthase inhibitor), wortmannin [phosphatidylinositol (PI) 3-kinase inhibitor], or (D-Lys(3))-GHRP-6 ( selective antagonist of ghrelin receptor GHSR-1a), as well as by knockdown of GHSR-1a using small-interfering ( si) RNA ( but not by mitogen/extracellular signal-regulated kinase inhibitor PD-98059). Moreover, ghrelin stimulated increased phosphorylation of Akt (Ser(473)) and eNOS ( Akt phosphorylation site Ser(1179)) that was inhibitable by knockdown of GHSR-1a using siRNA or by pretreatment of cells with wortmannin but not with PD-98059. Ghrelin also stimulated phosphorylation of mitogen-activated protein ( MAP) kinase in BAEC. However, unlike insulin, ghrelin did not stimulate MAP kinase-dependent secretion of the vasoconstrictor endothelin-1 from BAEC. We conclude that ghrelin has novel vascular actions to acutely stimulate production of NO in endothelium using a signaling pathway that involves GHSR-1a, PI3-kinase, Akt, and eNOS. Our findings may be relevant to developing novel therapeutic strategies to treat diabetes and related diseases characterized by reciprocal relationships between endothelial dysfunction and insulin resistance.