Matrix degrading proteases in vascular disease

Abstract

Diverse processes of vascular disease including lesion growth, plaque rupture and abdominal aortic aneurysm formation are influenced by protease expression. Arteries undergo compensatory remodelling when the mechanical forces that are imposed on them are altered. During growth of an atherosclerotic lesion there is an accumulation of inflammatory cells and extracellular matrix. The neointima formation with accumulation of macrophages and smooth muscle cells has been associated with increased amounts of proteases in the vascular wall. However, further investigation of the proteases are necessary to determine their diverse and overlapping roles in the progression of vascular disease.

In the present studies, we have identified three functional polymorphisms within the promoter regions of MMP-7 and MMP-12. In the MMP-7 promoter we found two polymorphisms located at -181 with an A to G substitution and the other one at -153 with a C to T substitution. Both of the MMP-7 polymorphisms were associated with a higher transcription rate in vitro together with smaller coronary artery luminal dimensions in vivo in a subgroup of hypercholesterolaemic patients. The MMP-12 promoter polymorphism is an A to G substitution located at -82. The polymorphism influences the binding of transcription factor activator protein-1, which is an important regulator of MMP transcription. Further, this allele specific regulation is influenced by insulin in vitro, and in a preliminary study, the polymorphism influenced luminal diameter in patients with diabetes.

When examining the differential expression of proteases during the progression of atherosclerosis, we found that the expression levels of cathepsins were high, and varied over time and location. In particular, cathepsins S showed an extensive expression in the fibrous plaque and medial smooth muscle cell layer. These results indicate that there may be a role for the cysteine and aspartic proteases in atherogenesis and plaque rupture.

When investigating the impact of functional polymorphisms in the promoter regions of three different MMPs on abdominal aortic aneurysm, we found that the growth rate of aneurysms appears to be influenced by a variation in the MMP-2 gene. These results indicate that there is a causative relationship between MMP-2 activity and abdominal aortic aneurysm progression.

Taken together, the results support the hypothesis that matrix-degrading proteases may influence the progression of vascular disease. In addition, we show that there are other proteases, the cathepsins, with a potential role in the process of atherosclerosis. Taken together, the importance of individual proteases seems to vary at different stages of vascular disease.