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(Circulation. 2004;110:II-268 – II-273.)
© 2004 American Heart Association, Inc.

Surgery for Aortic and Peripheral Vascular Disease

Effects of Deletion of the Tissue Inhibitor of Matrix Metalloproteinases-1 Gene on the Progression of Murine Thoracic Aortic Aneurysms

John S. Ikonomidis, MD PhD; William C. Gibson, MD; Jessica E. Butler, BS; David M. McClister, BS; Sarah E. Sweterlitsch, BS; Robert P. Thompson, PhD; Rupak Mukherjee, PhD; Francis G. Spinale, MD PhD

From Cardiothoracic Surgical Research, Division of Cardiothoracic Surgery (J.S.I., W.C.G., J.E.B., D.M.M., S.E.S., R.M., F.G.S.), and Department of Anatomy and Cell Biology (R.P.T.), Medical University of South Carolina, and the Ralph H. Johnson Veterans Affairs Medical Center (J.S.I., W.C.G., J.E.B., D.M.M., S.E.S., R.M., F.G.S.), Charleston, SC.

Correspondence to John S. Ikonomidis, MD, PhD, Assistant Professor of Surgery, Division of Cardiothoracic Surgery, Medical University of South Carolina, Suite 409 CSB, 96 Jonathan Lucas Street, Charleston, SC 29425. E-mail ikonomij{at}musc.edu

Objective— The cause of thoracic aortic aneurysms (TAAs) is poorly understood. Previous work has suggested an association between development of aortic aneurysms and matrix metalloproteinase (MMP) activity. We hypothesized that removal of the primary endogenous aortic MMP inhibitor (TIMP) through TIMP-1 gene deletion will increase TAA progression.

Methods and Results— The descending thoracic aortas of wild-type 129 SvE and TIMP-1 gene knockout (TIMP-1^–/–) mice were exposed to 0.5 mol/L CaCl₂ for 15 minutes, with terminal studies performed at 4 or 8 weeks. TAA lumen diameter was measured using confocal microscopy and normalized to the ascending aorta. In addition, sections were studied with in situ zymography and immunohistochemistry staining for MMP-9. Both wild-type [TAA/ascending ratio (mean±SEM): control, 0.85±0.02 (n=14); 4 weeks, 1.00±0.03 (n=13); 8 weeks, 1.05±0.10 (n=9)] and TIMP-1^–/– [control, 0.98±0.04 (n=11); 4 weeks, 1.10±0.03 (n =21); 8 weeks, 1.22±0.09 (n=10)] groups developed aneurysms at 4 and 8 weeks compared with their respective controls (P<0.05). TIMP-1^–/– animals developed larger aneurysms than the corresponding wild-type group (P<0.05). Aneurysms in the TIMP-1^–/– group were larger at 8 weeks than at 4 weeks (P<0.05), which was not seen in the wild-type aneurysm groups. Both groups showed presence of MMP-9 in 4 and 8 weeks, most prominently in the adventitia and outer media. In situ zymographic activity was increased in the 8-week TIMP-1^–/– group compared with wild-type.

Conclusions— Deletion of the TIMP-1 gene results in increased and continued progression of aneurysm formation compared with wild-type mice in a unique TAA model caused at least in part by an alteration in the balance between gelatinase activity and its endogenous inhibition. Therapeutic strategies aimed at modifying MMP activity may reduce or prevent the progression of TAAs.

Key Words: mouse • aneurysm • aorta • thorax • TIMP-1