on June 10, 2004
Published online before print June 10, 2004, doi: 10.1161/01.ATV.0000135656.49158.95
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Submitted on February 26, 2004
Accepted on May 27, 2004
Matrix Metalloproteinase-9 Genotype Influences Large Artery Stiffness Through Effects on Aortic Gene and Protein Expression
Tanya L. Medley ;
From the Alfred and Baker Medical Unit (T.L.M., A.M.D., C.D.G., B.A.K.), Baker Heart Research Institute, Prahran, and the Department of Biochemistry and Molecular Biology (T.J.C.), University of Melbourne, Victoria, Australia.
* To whom correspondence should be addressed. E-mail: b.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.
Key words: matrix metallproteinase • coronary artery disease • large artery stiffness • pulse pressure
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