LY290181, an inhibitor of diabetes-induced vascular dysfunction, blocks protein kinase C-stimulated transcriptional activation through inhibition of transcription factor binding to a phorbol response element

被引:37
作者
Birch, KA
Heath, WF
Hermeling, RN
Johnston, CM
Stramm, L
Dell, C
Smith, C
Williamson, JR
ReifelMiller, A
机构
[1] ELI LILLY & CO, LILLY CORP CTR, ENDOCRINOL RES, INDIANAPOLIS, IN 46285 USA
[2] LILLY RES CTR LTD, WINDLESHAM GU20 6PH, SURREY, ENGLAND
[3] UNIV WASHINGTON, SCH MED, DEPT PATHOL, ST LOUIS, MO USA
关键词
D O I
10.2337/diabetes.45.5.642
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Previous studies have shown that high glucose levels and diabetes induce an elevation in protein kinase C (PKC) activity in vascular cells and tissues susceptible to diabetic complications, In addition, PKC activation has been shown to modulate vascular cell growth, permeability, and gene expression, processes thought to be involved in the development of vascular complications, Using two in vivo model systems, we have identified a novel inhibitor of diabetic vascular dysfunction, LY290181, LY290181 prevented glucose-induced increases in blood flow and permeability in rat granulation tissue and corresponding vascular changes in the retina, sciatic nerve, and aorta of diabetic rats, Tested for its ability to inhibit PKC-regulated processes, LY290181 inhibited phorbol ester-stimulated plasminogen activator activity in a dose-dependent manner in bovine retinal endothelial cells and in human dermal fibroblasts, In addition, LY290181 inhibited phorbol ester-stimulated activation of the porcine urokinase plasminogen activator (uPA) promoter (-4600/+398) linked to the chloramphenicol acetyltransferase (CAT) reporter gene (p4660CAT), More detailed analysis of the uPA promoter revealed that LY290181 inhibited phorbol ester-stimulated activation of the uPA phorbol response element (-2458/-2349) located upstream of the thymidine kinase promoter (puPATKCAT), LY290181 appears to inhibit uPA promoter activation by blocking phorbol ester-stimulated binding of nuclear proteins to the uPA PEA3/12-O-tetradecanoylphorbol 13-acetate responsive element (TRE), These results suggest that LY290181 may inhibit diabetes-induced vascular dysfunction by inhibiting transcription factor binding to specific PKC-regulated genes involved in vascular function.
引用
收藏
页码:642 / 650
页数:9
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