罗格列酮对链脲佐菌素诱导的糖尿病大鼠和培养的内皮细胞内皮的保护作用与内源性一氧化氮合酶抑制剂之间的关系。

Relationship between protective effects of rosiglitazone on endothelium and endogenous nitric oxide synthase inhibitor in streptozotocin-induced diabetic rats and cultured endothelial cells.

作者信息

Wang Shan, Jiang Jun-Lin, Hu Chang-Ping, Zhang Xiao-Jie, Yang Dong-Liang, Li Yuan-Jian

机构信息

Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410078, China.

出版信息

Diabetes Metab Res Rev. 2007 Feb;23(2):157-64. doi: 10.1002/dmrr.662.

DOI:10.1002/dmrr.662

PMID:16770837

Abstract

BACKGROUND

Previous investigations have indicated that the level of asymmetric dimethylarginine (ADMA) is increased in diabetic patients and animals, and rosiglitazone has a protective effect on the endothelium. In the present study, we tested the relationship between protective effects of rosiglitazone and ADMA in streptozotocin (STZ)-induced diabetic rats and cultured endothelial cells.

METHODS

Blood samples were collected from carotid artery. Vasodilator responses to acetylcholine (ACh) in the isolated aortic rings were measured, and serum concentrations of glucose, lipid, nitrite/nitrate, ADMA and tumour necrosis factor-alpha (TNF-alpha) were determined. Cultured endothelial cells were treated with ADMA, and the concentrations of intercellular adhesion molecule (ICAM-1), TNF-alpha, and the activity of nuclear factor-kappaB (NF-kappaB) were determined.

RESULTS

Vasodilator responses to ACh were decreased markedly and the serum concentrations of TNF-alpha, nitrite/nitrate and ADMA were increased significantly in diabetic rats. Rosiglitazone (3, 10 or 30 mg/kg) produced a significant reduction of the inhibition of vasodilator responses to ACh, but had no effect on the serum concentrations of glucose, lipid, nitrite/nitrate and ADMA in diabetic rats. ADMA (30 microM) significantly increased the activity of NF-kappaB and elevated the levels of ICAM-1 and TNF-alpha, and pre-treatment with rosiglitazone (10 or 30 microM) markedly inhibited the increased activity of NF-kappaB and reduced the elevated levels of TNF-alpha and ICAM-1 induced by ADMA in cultured endothelial cells.

CONCLUSIONS

Rosiglitazone improves endothelial function in diabetic rats, which is related to the reduction of the inflammatory response induced by ADMA.

摘要

背景

先前的研究表明，糖尿病患者和动物体内不对称二甲基精氨酸（ADMA）水平升高，而罗格列酮对内皮具有保护作用。在本研究中，我们检测了罗格列酮在链脲佐菌素（STZ）诱导的糖尿病大鼠和培养的内皮细胞中的保护作用与ADMA之间的关系。

方法

从颈动脉采集血样。测量离体主动脉环对乙酰胆碱（ACh）的血管舒张反应，并测定血清中的葡萄糖、脂质、亚硝酸盐/硝酸盐、ADMA和肿瘤坏死因子-α（TNF-α）浓度。用ADMA处理培养的内皮细胞，并测定细胞间黏附分子（ICAM-1）、TNF-α的浓度以及核因子-κB（NF-κB）的活性。

结果

糖尿病大鼠对ACh的血管舒张反应明显降低，血清TNF-α、亚硝酸盐/硝酸盐和ADMA浓度显著升高。罗格列酮（3、10或30mg/kg）可显著减轻对ACh血管舒张反应的抑制，但对糖尿病大鼠血清中的葡萄糖、脂质、亚硝酸盐/硝酸盐和ADMA浓度无影响。ADMA（30μM）可显著增加NF-κB的活性，并升高ICAM-1和TNF-α的水平，而用罗格列酮（10或30μM）预处理可显著抑制ADMA诱导的培养内皮细胞中NF-κB活性的增加，并降低TNF-α和ICAM-1升高的水平。