Allele-specific regulation of matrix metalloproteinase-7 promoter activityis associated with coronary artery luminal dimensions among hypercholesterolemic patients

An enhanced expression of matrix metalloproteinase (MMP)-7 has previously b een demonstrated in atherosclerotic and aneurysmal tissue. Because perturbe d regulation of MMP-7 may influence the development of these diseases, we s earched the MMP-7 promoter for functional polymorphisms. An A to G substitu tion 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 identifie d. Allele-specific associations were studied in 350 patients undergoing per cutaneous transluminal coronary angioplasty. Hypercholesterolemic patients carrying the -181G allele or the -153T allele had smaller reference luminal diameters before percutaneous transluminal coronary angioplasty. Reverse t ranscription-polymerase chain reaction demonstrated that expression of MMP- 7 was confined to differentiated U937 cells. Northern blot analysis could n ot detect an effect of native or oxidatively modified low density lipoprote in 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 macrophag es within the vessel wall. Both polymorphisms influenced the binding of nuc lear proteins. Furthermore, in transient transfection studies, the combinat ion of the 2 rare alleles conferred an increased promoter activity. In conc lusion, the present study identified and characterized 2 common polymorphis ms in the promoter region of the MMP-7 gene that are functional in vitro an d seem to influence coronary arterial dimensions in hypercholesterolemic pa tients with manifest coronary artery disease.