title: Allele-specific regulation of matrix metalloproteinase-12 gene activity is associated with coronary artery luminal dimensions in diabetic patients with manifest coronary artery disease.
abstract: 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.
authors.affiliation: Atherosclerosis Research Unit, King Gustaf V Research Institute, Department of Medicine, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden. sofiaj@instmed.ks.se
authors.forename: S
authors.initials: S
authors.lastname: Jormsjö
authors.forename: S
authors.initials: S
authors.lastname: Ye
authors.forename: J
authors.initials: J
authors.lastname: Moritz
authors.forename: D H
authors.initials: DH
authors.lastname: Walter
authors.forename: S
authors.initials: S
authors.lastname: Dimmeler
authors.forename: A M
authors.initials: AM
authors.lastname: Zeiher
authors.forename: A
authors.initials: A
authors.lastname: Henney
authors.forename: A
authors.initials: A
authors.lastname: Hamsten
authors.forename: P
authors.initials: P
authors.lastname: Eriksson
mesh_terms: D000328:Adult; D000483:Alleles; D015906:Angioplasty, Balloon, Coronary; D000818:Animals; D002478:Cells, Cultured; D017023:Coronary Angiography; D003327:Coronary Disease / Q000201:enzymology* / Q000235:genetics / Q000628:therapy; D003925:Diabetic Angiopathies / Q000201:enzymology* / Q000235:genetics / Q000628:therapy; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics*; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D008297:Male; D053508:Matrix Metalloproteinase 12; D008666:Metalloendopeptidases / Q000235:genetics*; D051379:Mice; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D015607:Stents; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D007328:Insulin; D018808:Transcription Factor AP-1; D008666:Metalloendopeptidases; C507122:MMP12 protein, human; D053508:Matrix Metalloproteinase 12; D013755:Tetradecanoylphorbol Acetate