Department of Molecular Medicine, University of South Florida, Morsani College of Medicine, Tampa, FL, USA.
Biochem Biophys Res Commun. 2012 Apr 27;421(1):9-14. doi: 10.1016/j.bbrc.2012.03.074. Epub 2012 Mar 20.
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.
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型一氧化氮合酶（eNOS）来维持内皮细胞 NO 的产生，还通过调节精氨酸琥珀酸合成酶（AS）来维持，AS 是瓜氨酸-NO 循环的限速步骤。我们使用血清饥饿培养的血管内皮细胞表明，胰岛素可上调 AS 和 eNOS 转录以支持 NO 的产生。此外，我们还表明，胰岛素增强了对缓激肽等生理信号的 NO 产生反应。为了将这些结果转化为体内模型，我们表明，链脲佐菌素（STZ）诱导的糖尿病大鼠冠状动脉内皮细胞中的 AS 转录减少。重要的是，我们证明了胰岛素治疗可恢复 STZ 糖尿病大鼠的 AS 和 eNOS 转录，并且这种恢复伴随着内皮功能的改善，这可通过内皮依赖性血管舒张来衡量。总的来说，本报告在细胞培养和整体动物研究中均表明，胰岛素通过维持 AS 转录来维持血管功能，从而确保有足够的精氨酸供应来维持血管内皮对生理信号的反应。
