波动性高糖诱导内皮功能失调机制及葛根-丹参药对改善作用研究

Endothelial dysfunction (ED) is the common pathological basis various cardiovascular diseases. Oscillations of blood glucose concentration and chronic diabetic vascular complications are common clinical phenomenon in diabetic patients. The herb pair Radix Puerariae-Salvia miltiorrhiza Bunge is widely used in clinical for diabetic vascular complications treatment while the underlying mechanisms remain unclear. Our studies showed that the endothelial NADPH oxidase-LOX-1 pathway played important roles in ED. Furthermore, the herb pair Radix Puerariae-Salvia miltiorrhiza Bunge significantly improve STZ-induced pathological changes in aorta, decreased oxidative stress, and dramatically inhibited the protein expression of NOX2, NOX4, and LOX-1. This suggests that the NADPH oxidase-LOX-1 pathway may play important roles in the beneficial effect of the herb pair. Therefore, with cellular and animal models, this proposal will further investigate the molecular mechanisms of endothelial NADPH oxidase-LOX-1 pathway activation by oscillated high glucose and its pathological significance in diabetic vascular diseases. Furthermore, the molecular mechanisms and pathological significance of the herb pair Radix Puerariae-Salvia miltiorrhiza Bunge in improving diabetic aortic lesions will be explored. The results will enrich the "glucose toxicity" theory and provide scientific data for the clinical application of Radix Puerariae-Salvia miltiorrhiza Bunge pair.

内皮功能失调（ED）是心血管疾病的共同病理基础之一，血糖波动、慢性血管病变是临床糖尿病患者常见病症。葛根-丹参药对临床广泛用于改善糖尿病血管病变，但分子机制尚不明确。我们前期研究显示内皮NADPH氧化酶-LOX-1通路在ED中起重要作用；葛根-丹参药对显著改善STZ诱导糖尿病小鼠主动脉病变、降低氧化应激、抑制主动脉NOX2、NOX4、LOX-1蛋白表达。这提示NADPH氧化酶-LOX-1通路在葛根-丹参药对改善糖尿病血管病变中起重要作用。本研究将利用内皮细胞模型研究波动性高糖激活内皮NADPH氧化酶-LOX-1通路的分子机制，并结合STZ诱导的糖尿病模型探讨葛根-丹参药对的抑制作用。这将丰富高糖诱导的“糖毒性”理论，为葛根-丹参药对的临床应用提供科学数据支持。

内皮功能失调（ED）是心血管疾病的共同病理基础之一，血糖波动、慢性血管病变是临床糖尿病患者常见病症。葛根-丹参药对临床广泛用于改善糖尿病血管病变的中药药对，但其作用的具体分子机制尚不明确。本项目利用高糖诱导的内皮细胞模型，研究了高糖对内皮NADPH氧化酶表达的影响，探讨了NADPH氧化酶在诱导内皮LOX-1表达中的作用，并利用链脲佐菌素（STZ）诱导的糖尿病大鼠模型，探讨了葛根-丹参药对的抑制作用。结果发现：1）波动性高糖能显著增强内皮细胞NADPH 氧化酶的表达，尤其是NOX4的表达明显； 2）波动性高糖能显著诱导内皮细胞LOX-1的表达；3）波动性高糖激活内皮NADPH氧化酶诱导LOX-1表达的机制可能是通过诱导内皮活性氧（ROS）生成。 4）葛根-丹参提取物能明显抑制糖尿病模型血管病变，抑制NOX4、 NOX2的表达。本研究丰富高糖了诱导的内皮“糖毒性”理论，揭示了中药药对葛根-丹参防治糖尿病血管病变的分子机制，为该药对的临床应用提供科学数据支持。