Abstract 3708: Effects of Tissue Inhibitor of Metalloproteinase (TIMP) Deficiency on Macrophage Infiltration, Plaque Stability and Pseudo-Aneurysms
Matrix metalloproteinases are postulated to precipitate atherosclerotic plaque progression and instability. However, the role of tissue inhibitor of metalloproteinases (TIMP) remains unclear. In an attempt to address this issue, atherosclerotic lesions were investigated in mice with a single or double deficiency of apolipoprotein E (apoE) and either TIMP-1 or TIMP-2, fed a high-fat diet for 8 weeks. Analysis of brachiocephalic artery plaques revealed that loss of TIMP-1 or TIMP-2 had no effect on lesion area, compared with age-matched, strain-matched apoE knockout controls. However, lesions from apoE/TIMP-2 double knockout animals exhibited decreased macrophage:SMC ratio (p<0.0001), reduced number of proliferating macrophages (p<0.01), increased collagen content (p<0.01) and reduced frequency of buried fibrous caps (p<0.001), compared to apoE single knockout controls. Additionally, macrophages from TIMP-2 double knockout mice had a significantly reduced ability to infiltrate Matrigel-infused subcutaneous sponges (p<0.001). Moreover, pseudo-aneurysm formation was also attenuated beneath lesions from apoE/TIMP-2 double knockout animals (p<0.001). Despite a significant reduction in SMC content (p<0.01), lesions from apoE/TIMP-1 double knockouts did not differ in any other parameters compared to control animals. Controversially, these data suggest that endogenous levels of TIMP-2 promote atherosclerotic plaque instability and increase pseudo-aneurysm formation, possibly through modulation of macrophage recruitment to atherosclerotic lesions.