中国动脉硬化杂志2011，Vol.19Issue(10)：795-801,7.
SP600125对1型糖尿病小鼠颈动脉内皮功能及单核细胞趋化蛋白1表达的影响
The Effect of SP600125 on Endothelial Function and Monocyte Chemotactic Protein-1 Expression in Carotid Artery in Type 1 Diabetic Mice
摘要
Abstract
Aim The incidence of stroke in diabetes is increasing seriously, which is associated with endothelial dysfunction and increased inflammation in carotid artery.Our study is to investigate the effect of c-Jun arnino-terminal ki-nase (JNK) specific inhibitor SP600125 on carotid endothelial function and monocyte chemotactic protein-1 (MCP-1) expression in type 1 diabetes. Methods Animals were divided into five groups in this study. The 1st group was C57BL/6 wild type male mice; the 2nd group was INS2AKUTI male mice, intraperitoneal injection with 0. 9% normal saline (NS) each day for 8 weeks; the 3rd, 4th, 5th group were INS2AKITA male mice, intraperitoneal injection with SP600125 10 mg/kg, 20 mg/kg, 30 mg/kg respectively each day for consecutive 8 weeks. Then the mice were killed and sreum my-eloperoxidase (MPO) , malondialdehyde (MDA) , nitric oxide (NO) , total nitric oxide synthase (TNOS) were measured. HE staining was performed in carotid artery and immunohistochemistry was performed to investigate MCP-1 protein expression in endothelial cells of carotid artery. P-JNK, JNK, MCP-1 protein expression in carotid artery was measured by Western blot, signal transducer and activator of transcription-1 (STAT-1) DNA binding activity was assayed by electro-phoretic mobility shift assay (EMSA). Results Compared with wild type mice, serum MPO and MDA expression increased prominently (P <0. 05) , whereas TNOS, NO decreased and p-JNK/JNK, MCP-1 expression increased significantly in INS2AKITA mice (P<0.05); STAT-1 DNA binding activity increased prominently in type 1 diabetic group compared with that in control group (P <0. 05). Compared with type 1 diabetic mice, after treatment with SP600125, MPO decreased and NO, TNOS increased and p-JNK/JNK, endothelial MCP-1 expression decreased (P<0. 05). The effects of SP600125 on MPO, NO, TNOS, MCP-1 were increased accordingly as the dose of SP600125 increased. As the dose of SP600125 increased, MCP-1 protein expression decreased 21. 82% ,39. 09% ,68. 18% respectively; STAT-1 DNA binding activity decreased 25. 70% ,33. 20% ,61. 29% respectively compared with type 1 diabetic mice. Conclusions JNK specific inhibitor SP600125 could inhibit STAT-1 DNA binding activity, thus increase serum NO and TNOS, and improve carotid diastolic function. SP6O0125 could also decrease MCP1 and MPO in a dose-dependent manner. The results also showed JNK signal pathway is associated with carotid endothelial dysfunction and inflammatory expression via activation of STAT-1 in type 1 diabetes. Our study provides a novel pharmacologie agent to prevent the promotion of macrovascular complication in type 1 diabetes.关键词
1型糖尿病/颈动脉/JNK信号通路/信号转导子和转录激活子1/单核细胞趋化蛋白1Key words
Type 1 Diabetes/Carotid Artery/c-Jun Ammo-terminal Kinase Signal Pathway/Signal Transducer and Activator of Transcription-1/Monocyte Chemotactic Protein-1分类
医药卫生引用本文复制引用
王启章,陈茂刚,李达文,刘朝来,徐格林,刘新峰..SP600125对1型糖尿病小鼠颈动脉内皮功能及单核细胞趋化蛋白1表达的影响[J].中国动脉硬化杂志,2011,19(10):795-801,7.基金项目
国家自然科学基金(青年基金)项目(81000502)及江苏省科技计划项目(BK2009319)资助 （青年基金）
