Insulin transcriptionally regulates argininosuccinate synthase to maintain vascular endothelial function.
Insulin transcriptionally regulates argininosuccinate synthase to maintain vascular endothelial function.
复制标题
胰岛素转录调节精氨酸琥珀酸合酶以维持血管内皮功能。
DOI：
10.1016/j.bbrc.2012.03.074
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发表时间：
2012
影响因子：
3.1
通讯作者：
Eichler,DuaneC
中科院分区：
文献类型：
--
作者：
Haines,RicciJ;Corbin,KarenD;Pendleton,LauraC;Meininger,CynthiaJ;Eichler,DuaneC
血管内皮细胞一氧化氮（NO）生成减少是糖尿病复杂发病机制的一个主要因素。在本报告中，我们证明胰岛素不仅通过调节内皮一氧化氮合酶（eNOS）来维持内皮NO的产生，而且还通过调节精氨酸琥珀酸合酶（AS）来维持内皮NO的产生，精氨酸琥珀酸合酶（AS）是瓜氨酸-NO循环的限速步骤。使用血清饥饿培养的血管内皮细胞，我们发现胰岛素上调 AS 和 eNOS 转录以支持 NO 产生。此外，我们发现胰岛素会响应缓激肽等生理信号而增强一氧化氮的产生。为了将这些结果转化为体内模型，我们发现从链脲佐菌素 (STZ) 诱导的糖尿病大鼠中分离的冠状动脉内皮细胞中 AS 转录减少。重要的是，我们证明了通过胰岛素治疗 STZ 糖尿病大鼠可以恢复 AS 和 eNOS 转录，并且通过内皮依赖性血管舒张来测量，这种恢复伴随着内皮功能的改善。总体而言，该报告表明，在细胞培养和整体动物研究中，胰岛素部分通过维持 AS 转录来维持血管功能，从而确保精氨酸的充足供应以维持血管内皮对生理信号的反应。
Diminished vascular endothelial cell nitric oxide (NO) production is a major factor in the complex pathogenesis of diabetes mellitus. In this report, we demonstrate that insulin not only maintains endothelial NO production through regulation of endothelial nitric oxide synthase (eNOS), but also via the regulation of argininosuccinate synthase (AS), which is the rate-limiting step of the citrulline–NO cycle. Using serum starved, cultured vascular endothelial cells, we show that insulin up-regulates AS and eNOS transcription to support NO production. Moreover, we show that insulin enhances NO production in response to physiological cues such as bradykinin. To translate these results to an in vivo model, we show that AS transcription is diminished in coronary endothelial cells isolated from rats with streptozotocin (STZ)-induced diabetes. Importantly, we demonstrate restoration of AS and eNOS transcription by insulin treatment in STZ-diabetic rats, and show that this restoration was accompanied by improved endothelial function as measured by endothelium-dependent vasorelaxation. Overall, this report demonstrates, both in cell culture and whole animal studies, that insulin maintains vascular function, in part, through the maintenance of AS transcription, thus ensuring an adequate supply of arginine to maintain vascular endothelial response to physiological cues.