Enhanced abdominal aortic aneurysm in TIMP-1-deficient mice

Matrix metalloproteinases (MMPs) are known elastolytic mediators of abdominal aortic aneurysm (AAA) degeneration, and their activity is tightly regulated by the presence of tissue inhibitors of MMPs (TIMPs). Imbalances in this system may be instrumental in compromising arterial wall integrity. The aim of this study was to show that, in an elastase-induced murine model of aneurysm formation, TIMP-1 has a protective effect. Twenty-four wild-type (TIMP-1 ^+/+) and 22 knockout (TIMP-1^-/-) mice underwent laparotomy and isolation of the infrarenal aorta. A polyethylene catheter was inserted into the aorta and dilute pancreatic elastase (0.39 Units/ml) was infused over 5 min using a perfusion pump. Pre- and postinfusion maximal aortic diameters were obtained in triplicate for each animal using NIH Image. Final aortic measurements were obtained 14 days later, prior to perfusion fixation with 10% buffered Formalin. Aortic specimens were sectioned and stained. Statistical analysis was performed using the Student's t test. TIMP-1^-/- mice demonstrated a significant postinfusion diameter increase compared to wild-types after elastase, which was not seen after saline infusion. At sacrifice, TIMP-1^-/- mice, following both saline and elastase infusion, showed a significant increase in maximal aortic diameter relative to postinfusion measurements compared to TIMP-1^+/+ mice. TIMP-1^-/- mice develop larger aneurysms than TIMP-1^+/+ mice. This study illustrates the protective effects of TIMP-1 in an experimental AAA model and may provide a means for pharmacologically controlling aneurysm growth.