Rosiglitazone stimulates nitric oxide synthesis in human aortic endothelial cells via AMP-activated protein kinase
Rosiglitazone stimulates nitric oxide synthesis in human aortic endothelial cells via AMP-activated protein kinase
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DOI：
10.1074/jbc.m710048200
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发表时间：
2008-04-25
影响因子：
4.8
通讯作者：
Salt, Ian P.
中科院分区：
文献类型：
--
作者：
Boyle, James G.;Logan, Pamela J.;Salt, Ian P.
噻唑烷二酮类抗糖尿病药物通过Ser-1177的磷酸化增加内皮一氧化氮（NO）合酶的活化，并增加NO的生物利用度，但其分子机制仍不清楚。已经证明了几种蛋白激酶，包括AMP活化的蛋白激酶，在Ser-1177磷酸化内皮NO合酶。在目前的研究中，我们确定的作用，腺苷酸激活的蛋白激酶在罗格列酮刺激NO的合成。用罗格列酮刺激人主动脉内皮细胞导致AMP活化蛋白激酶活性和NO产生的时间和剂量依赖性刺激，伴随着内皮NO合酶Ser-1177的磷酸化。罗格列酮刺激ADP/ATP比值在内皮细胞中的增加，和LKB 1是必不可少的罗格列酮刺激的AMPK活性在HeLa细胞。用编码显性负性AMP激活蛋白激酶突变体的病毒感染内皮细胞，可消除罗格列酮刺激的Ser-1177磷酸化和NO产生。此外，AMP激活的蛋白激酶和NO合成的罗格列酮的刺激不受过氧化物酶体增殖物激活受体-γ抑制剂GW 9662。这些研究表明，罗格列酮能够通过AMP激活的蛋白激酶依赖性机制（可能由LKB 1介导）急性刺激培养的内皮细胞中的NO合成。
The thiazolidinedione anti-diabetic drugs increase activation of endothelial nitric-oxide (NO) synthase by phosphorylation at Ser-1177 and increase NO bioavailability, yet the molecular mechanisms that underlie this remain poorly characterized. Several protein kinases, including AMP-activated protein kinase, have been demonstrated to phosphorylate endothelial NO synthase at Ser-1177. In the current study we determined the role of AMP-activated protein kinase in rosiglitazone-stimulated NO synthesis. Stimulation of human aortic endothelial cells with rosiglitazone resulted in the time- and dose-dependent stimulation of AMP-activated protein kinase activity and NO production with concomitant phosphorylation of endothelial NO synthase at Ser-1177. Rosiglitazone stimulated an increase in the ADP/ATP ratio in endothelial cells, and LKB1 was essential for rosiglitazone-stimulated AMPK activity in HeLa cells. Infection of endothelial cells with a virus encoding a dominant negative AMP-activated protein kinase mutant abrogated rosiglitazone-stimulated Ser-1177 phosphorylation and NO production. Furthermore, the stimulation of AMP-activated protein kinase and NO synthesis by rosiglitazone was unaffected by the peroxisome proliferator-activated receptor-gamma inhibitor GW9662. These studies demonstrate that rosiglitazone is able to acutely stimulate NO synthesis in cultured endothelial cells by an AMP-activated protein kinase-dependent mechanism, likely to be mediated by LKB1.