Allele-specific regulation of matrix metalloproteinase-7 promoter activity is associated with coronary artery luminal dimensions among hypercholesterolemic patients.
An enhanced expression of matrix metalloproteinase (MMP)-7 has previously been demonstrated in atherosclerotic and aneurysmal tissue. Because perturbed regulation of MMP-7 may influence the development of these diseases, we searched the MMP-7 promoter for functional polymorphisms. An A to G substitution at position -181 (-181 A/G) and a C to T substitution at position -153 (-153 C/T) with frequencies of 0.50 and 0.10, respectively, were identified. Allele-specific associations were studied in 350 patients undergoing percutaneous transluminal coronary angioplasty. Hypercholesterolemic patients carrying the -181G allele or the -153T allele had smaller reference luminal diameters before percutaneous transluminal coronary angioplasty. Reverse transcription-polymerase chain reaction demonstrated that expression of MMP-7 was confined to differentiated U937 cells. Northern blot analysis could not detect an effect of native or oxidatively modified low density lipoprotein on MMP-7 expression. Thus, the limitation of allele-specific effects on vessel wall remodeling to hypercholesterolemic patients may be secondary to lipid-mediated accumulation of MMP-7-expressing monocyte-derived macrophages within the vessel wall. Both polymorphisms influenced the binding of nuclear proteins. Furthermore, in transient transfection studies, the combination of the 2 rare alleles conferred an increased promoter activity. In conclusion, the present study identified and characterized 2 common polymorphisms in the promoter region of the MMP-7 gene that are functional in vitro and seem to influence coronary arterial dimensions in hypercholesterolemic patients with manifest coronary artery disease.
Jormsjö
S
S
Atherosclerosis Research Unit, King Gustaf V Research Institute, Department of Medicine, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden.
Whatling
C
C
Walter
D H
DH
Zeiher
A M
AM
Hamsten
A
A
Eriksson
P
P
D000328:Adult; D000483:Alleles; D003324:Coronary Artery Disease / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D003331:Coronary Vessels / Q000473:pathology*; D005838:Genotype; D006801:Humans; D006937:Hypercholesterolemia / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism; D020783:Matrix Metalloproteinase 7 / Q000096:biosynthesis / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D015533:Transcriptional Activation; D020298:U937 Cells
D008077:Lipoproteins, LDL; D012333:RNA, Messenger; C099252:oxidized low density lipoprotein; D020783:Matrix Metalloproteinase 7