The role of inflammation in the expression of matrix metalloproteases in abdominal aortic aneurysms
A.1 Background. Abdominal aortic aneurysms are a common and life-threatening condition. At present, major surgery is the only treatment available, and a pharmacotherapy would be desirable both to reduce aneurysm expansion and rupture rates. In this thesis, the literature was reviewed in order to understand and aneurysm pathogenesis, and matrix metalloprotease (MMP) activity and inflammation were identified as key targets. Drugs that might affect these targets were then investigated in vitro using both human aortic explant cultures and a porcine model of aneurysmal disease. Once simvastatin had been shown to have beneficial effects on these processes, a double-blinded, randomised and controlled clinical trial was initiated. A.2 Methods. Human aortic explant cultures were used to investigate the effect of various drugs on cytokine production by human aortic tissue. The porcine model was used to examine the effect on matrix metalloprotease activity by gel zymography. Finally, patients undergoing aneurysm repair were recruited into a randomised trial to look at the effects of simvastatin on aneurysms in vivo. A.3 Results. Rofecoxib failed to demonstrate beneficial effects on aneurysms development. Simvastatin reduced the secretion of interleukin-6 (a marker of inflammation) from 108.3 (73-139.5) ng/ml to 35 (13-72.6) ng/ml (p=0.003). Simvastatin also reduced the activity of both the active and proenzyme forms of MMP-2 and MMP-9 (proenzyme MMP-2, p=0.027; active MMP-2, p<0.01; proenzyme MMP-9, p=0.013; active MMP-9, p=0.016). In the clinical trial, simvastatin reduced the activity of the proenzyme form of MMP-9 (p=0.007). A.4 Discussion. Simvastatin reduced both MMP activity and the secretion of IL-6 in laboratory studies on aneurysmal tissue. Although recruitment for the clinical trial had to be curtailed for ethical reasons, some beneficial effects were also demonstrated in vivo. These findings add to the evidence that patients with aneurysms should be prescribed a statin.