Transcriptional regulation of TIMPs in ascending aorta aneurysms

The events that result in the establishment and progression of aortic aneurysms are complex and multifactorial. However, degradation of the extracellular matrix (ECM) of aortic tunica media appears to be a consistent histopathological and biochemical feature. An increased local expression of matrix metalloproteinases (MMPs) as well as an imbalance between MMP expression and the expression of their natural tissue inhibitors (TIMPs) have been demonstrated in dilated aortic wall. We hypothesized that a distinct MMP and TIMP expression pattern underlies the development of ascending aorta dilation. To test our hypothesis, expression levels of 10 MMPs and 4 TIMPs were assessed by real-time PCR in dilated and normal aortic tissue derived from patients that underwent elective surgical repair of ascending aorta aneurysm (AAA) and coronary artery by-pass grafting, respectively. We found no statistically significant up- or down-regulation of any individual MMP. Surprisingly, the tissue inhibitor of metalloproteinases (TIMP)-3 was significantly more expressed in dilated aortic tissue compared to control tissue, thereby reflecting an effort to counteract MMP activity. Finally, when we evaluated the MMP and TIMP co-expression pattern in normal and dilated aortic tissue, we observed that in aortic aneurysms activation of the MMP system was characterised by the co-expression of more than one proteinase and the down-regulation of TIMP-1 and -2. The latter observation is the key regulatory point that leads to ECM degradation and, subsequently, to AAA formation.