Allele-Specific Regulation of Matrix Metalloproteinase-7 Promoter Activity Is Associated With Coronary Artery Luminal Dimensions Among Hypercholesterolemic Patients

Abstract

Abstract-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 Ϫ181 (Ϫ181 A/G) and a C to T substitution at position Ϫ153 (Ϫ153 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 Ϫ181G allele or the Ϫ153T 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. (Arterioscler Thromb Vasc

Matrix metalloproteinases and gastrointestinal cancers: Impacts of dietary antioxidants

“…Two common functional MMP-7 SNPs (-181A/G, -153C/T) are believed to control gene expression in several diseases, including gastrointestinal cancer [67][68][69] . MMP-7 up-regulation was significantly related to the promoter activity variation of the -181A/G alleles.…”

“…MMP-7 up-regulation was significantly related to the promoter activity variation of the -181A/G alleles. Jormsjö et al [68] reported that the expression and promoter activity of the MMP7 -181G allele was higher in G over A and, attributed to the formation of a putative binding site (NGAAN) for a heat-shock transcription factor to G-allele. On the contrary, Richards et al [69] reported that elevated plasma MMP-7 level in AA genotype was governed by the G to A transition in -181 bp resulting in higher binding for the forkhead box A2 transcription factor to AA genotype.…”

Association of MMP7 −181A→G Promoter Polymorphism with Gastric Cancer Risk

“…6), further strengthening the role of CREB in the MMP7 expression. In this context, it has been reported that the expression and promoter activity of the MMP7 Ϫ181G allele was 2-3-fold higher than the Ϫ181A allele in U937 cell type and was attributed to the formation of a putative binding site (NGAAN) for a heat-shock transcription factor in the case of the G-allele although not for the A-allele (25). On the contrary, elevated plasma MMP7 levels in AA genotype of idiopathic pulmonary fibrosis patients were governed by the G to A transition in the Ϫ181 site of the MMP7 promoter resulting in a novel binding site for the forkhead box A2 (FOXA2) transcription factor, which led to higher promoter activity in the case of the A allele (26).…”

“…Two common functional SNPs (Ϫ181A3 G and Ϫ153C/T) located in the MMP7 promoter region known to influence gene expression were studied in several disease conditions, including hypercholesterolemia, idiopathic pulmonary fibrosis, and several cancer types (e.g. breast, colon, and esophagus) (10,13,15,(25)(26)(27). Previous studies demonstrated a correlation between MMP7 Ϫ181A3 G substitution and gastric cancer susceptibility in Chinese and Caucasian populations (13,28).…”

Current Evidence on Associations Between the MMP-7 (-181A>G) Polymorphism and Digestive System Cancer Risk

“…The G allele has greater basal transcriptional activity than A allele in vitro experiment (Jormsjo et al, 2001). Over-expression of MMP7 has been shown to occur in a wide variety of cancers, including tumours of the oesophagus, stomach, colorectal, kidney and breast (Greenwald et al, 2002;Hodi et al, 2003), and this is correlated with tumor size, lymph node involvement and decreased survival.…”