Allele-specific regulation of matrix metalloproteinase-12 gene activity is associated with coronary artery luminal dimensions in diabetic patients with manifest coronary artery disease

被引:154
作者
Jormsjö, S [1 ]
Ye, S
Moritz, J
Walter, DH
Dimmeler, S
Zeiher, AM
Henney, A
Hamsten, A
Eriksson, P
机构
[1] Karolinska Hosp, King Gustaf V Res Inst, Atherosclerosis Res Unit, Dept Med,Karolinska Inst, S-17176 Stockholm, Sweden
[2] Univ Oxford, Dept Cardiovasc Med, Oxford OX1 2JD, England
[3] Univ Frankfurt, Dept Internal Med, D-6000 Frankfurt, Germany
关键词
metalloproteinase-12; matrix; polymorphism; insulin; activator protein-1;
D O I
10.1161/01.RES.86.9.998
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Both the processes of atherosclerosis and plaque rupture are indicated to be influenced by matrix metalloproteinase (MMP) activity. We therefore searched for common functional variation in the matrix metalloelastase (MMP-12) gene locus that may be implicated in coronary artery disease. Single-strand conformation polymorphism analysis of DNA from healthy individuals detected a common polymorphism within the MMP-12 gene promoter (an A-to-G substitution at position -82), The frequency of the G allele was 0.19. The polymorphism influences the binding of the transcription factor activator protein-1 (AP-1) in electromobility shift assay, A higher binding affinity of AP-1 to the A allele was associated with higher MMP-12 promoter activity in vitro in transient transfection studies in U937 and murine lung macrophage (MALU) cells. Phorbol 12-myristate 13-acetate (PMA) and insulin, 2 known activators of AP-1, increased the binding of AP-1 to the MMP-12 promoter, with higher affinity for the A allele. In transfection experiments, both the A and the G alleles responded to insulin and PMA, the A allele showing higher promoter activity than the G allele. Furthermore, Western blot analysis demonstrated that insulin increased MMP-12 protein production. To analyze whether the -82 A/G polymorphism is associated with coronary artery disease, 367 consecutive patients who underwent percutaneous transluminal coronary angiography with stent implantation were genotyped, In patients (n=71) with diabetes, the A allele was associated with a smaller luminal diameter. In conclusion, a common functional polymorphism within the MMP-12 promoter influences coronary artery luminal dimensions in diabetic patients with manifest coronary artery disease.
引用
收藏
页码:998 / 1003
页数:6
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