JDRF Einstein Centre for Diabetes Complications, Melbourne, Australia.
J Hypertens. 2010 Apr;28(4):780-8. doi: 10.1097/HJH.0b013e328335043e.
A number of factors contribute to diabetes-associated vascular dysfunction. In the present study, we tested whether exposure to advanced glycation end-products (AGEs) impairs vascular reactivity independently of hyperglycemia and examined the potential mechanisms responsible for diabetes and AGE-associated vascular dysfunction.
Vasodilator function was studied using infusion of exogenous AGEs into Sprague-Dawley rats as compared with control and streptozotocin-induced diabetic rats all followed for 16 weeks (n = 10 per group). The level of arginine metabolites and expression of endothelial nitric oxide synthase (eNOS) and downstream mediators of nitric oxide-dependent signaling were examined. To further explore these mechanisms, cultured bovine aortic endothelial cells (BAECs) were exposed to AGEs.
Both diabetic and animals infused with AGE-modified rat serum albumin (AGE-RSA) had significantly impaired vasodilatory response to acetylcholine. Unlike diabetes-associated endothelial dysfunction, AGE infusion was not associated with changes in plasma arginine metabolites, asymmetric dimethyl-L-arginine levels or eNOS expression. However, expression of the downstream mediator cGMP-dependent protein kinase 1 (PKG-1) was significantly reduced by both AGE exposure and diabetes. AGEs also augmented hyperglycemia-associated depletion in endothelial nitric oxide production and eNOS protein expression in vitro, and the novel AGE inhibitor, alagebrium chloride, partly restored these parameters.
We demonstrate that AGEs represent a potentially important cause of vascular dysfunction, linked to the induction of nitric oxide resistance. These findings also emphasize the deleterious and potentially additive effects of AGEs and hyperglycemia in diabetic vasculature.
许多因素导致与糖尿病相关的血管功能障碍。在本研究中，我们测试了暴露于晚期糖基化终产物（AGEs）是否会独立于高血糖损害血管反应性，并研究了导致糖尿病和 AGE 相关血管功能障碍的潜在机制。
通过向 Sprague-Dawley 大鼠输注外源性 AGEs 来研究血管舒张功能，与对照组和链脲佐菌素诱导的糖尿病大鼠进行比较，所有大鼠均随访 16 周（每组 10 只）。检查精氨酸代谢物的水平以及内皮型一氧化氮合酶（eNOS）和一氧化氮依赖信号转导的下游介质的表达。为了进一步探讨这些机制，将培养的牛主动脉内皮细胞（BAECs）暴露于 AGEs 中。
糖尿病大鼠和输注 AGE 修饰的大鼠血清白蛋白（AGE-RSA）的大鼠的乙酰胆碱舒张反应均明显受损。与糖尿病相关的内皮功能障碍不同，AGE 输注与血浆精氨酸代谢物、不对称二甲基-L-精氨酸水平或 eNOS 表达的变化无关。然而，下游介质 cGMP 依赖性蛋白激酶 1（PKG-1）的表达在 AGE 暴露和糖尿病时均显著降低。AGEs 还增强了体外高血糖相关的内皮一氧化氮产生和 eNOS 蛋白表达的耗竭，新型 AGE 抑制剂，alagebrium chloride，部分恢复了这些参数。
我们证明 AGEs 是血管功能障碍的一个潜在重要原因，与诱导一氧化氮抵抗有关。这些发现还强调了 AGEs 和高血糖在糖尿病血管中的有害和潜在的累加作用。
