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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:1479.)
© 2004 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Matrix Metalloproteinase-9 Genotype Influences Large Artery Stiffness Through Effects on Aortic Gene and Protein Expression

Tanya L. Medley; Timothy J. Cole; Anthony M. Dart; Christoph D. Gatzka; Bronwyn A. Kingwell

From the Alfred and Baker Medical Unit (T.L.M., A.M.D., C.D.G., B.A.K.), Baker Heart Research Institute, and the Department of Biochemistry and Molecular Biology (T.J.C.), University of Melbourne, Victoria, Australia.

Correspondence to Dr Bronwyn Kingwell, Alfred and Baker Medical Unit, Baker Medical Research Institute, P.O. Box 6492, St Kilda Road Central, Melbourne, Victoria, 8008, Australia (please use air mail). E-mailb.kingwell{at}alfred.org.au

Objective— Because large artery stiffening contributes to myocardial ischemia, its determinants are of relevance as potential risk markers. This study examined whether matrix metalloproteinase (MMP)-9 (gelatinase B) genotype is associated with large artery stiffening and aortic MMP-9 gene and protein expression.

Methods and Results— MMP-9 genotype (C-1562T promoter polymorphism) was determined in 84 patients (73 male) with angiographically defined coronary artery disease (CAD). Carotid applanation tonometry was used to assess central blood pressures and, with Doppler velocimetry, to assess aortic stiffness (input and characteristic impedance). Gene expression real-time polymerase chain reaction (RT-PCR) and protein levels (Western blotting) were assessed in relation to genotype in aortic samples from a separate population. T-allele carriers (C/T and T/T) had stiffer large arteries (higher input and characteristic impedance) and higher carotid pulse and systolic blood pressure (all P<0.05) than C/C homozygotes. In aortic samples, gene expression was 5-fold higher and active protein levels were >2-fold higher in T-allele carriers.

Conclusions— Because the T allele was associated with greater MMP-9 mRNA and protein levels, the greater large artery stiffness in T-allele carriers may be secondary to excessive degradation of the arterial elastic matrix. The consequent higher pulse pressure may increase susceptibility to myocardial ischemia.

Coronary artery disease patients that carry at least 1 copy of the MMP-9 T allele have stiffer large arteries compared with C/C homozygotes. This relationship may result from increased degradation of important elastic components of the extracellular matrix secondary to elevated MMP-9 gene expression and protein levels in the aorta.

Key Words: matrix metallproteinase • coronary artery disease • large artery stiffness • pulse pressure

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