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(Circulation. 2005;112:I-242 – I-248.)
© 2005 American Heart Association, Inc.

Myocardial Protection and Vascular Biology

Effects of Deletion of the Matrix Metalloproteinase 9 Gene on Development of Murine Thoracic Aortic Aneurysms

John S. Ikonomidis, MD, PhD; John R. Barbour, MD; Zainab Amani; Robert E. Stroud, MS; Amanda R. Herron, BS; David M. McClister, Jr, BS; Sarah E. Camens, BS; Merry L. Lindsey, PhD; Rupak Mukherjee, PhD; Francis G. Spinale, MD, PhD

From the Cardiothoracic Surgical Research, Division of Cardiothoracic Surgery, Medical University of South Carolina and the Ralph H. Johnson Veterans Affairs Medical Center (J.S.I., F.G.S.), Charleston, SC.

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

Background— The matrix metalloproteinases (MMPs) contribute to cardiovascular remodeling, and MMPs, such as the gelatinases (MMP-9 and MMP-2), have been identified in thoracic aortic aneurysmal (TAA) tissue, but a cause-effect relationship has not been clearly established. Accordingly, this study examined TAA progression in mice devoid of the MMP-9 gene.

Methods and Results— The descending thoracic aortas of wild-type (WT) FVB (n =17) and MMP-9 gene knockout (KO, n =11) mice were exposed to 0.5 mol/L of CaCl₂ for 15 minutes with terminal studies performed at 4 weeks. Aortic lumen diameter was measured using video micrometry at baseline and at 4 weeks (TAA) followed by aortic tissue analysis. In WT mice, aortic diameter increased by 138±5% at 4 weeks (P<0.05), consistent with TAA formation. In the KO mice, aortic diameter increased from baseline by 120±4% (P<0.05) but was attenuated from WT TAA values (P<0.05). Gelatin zymography performed on TAA segments confirmed the absence of MMP-9 in the KO mice but a >8-fold relative increase in the active form of MMP-2 compared with WT (P<0.05). Despite this, MMP-2 activity was relatively increased (P<0.05) and colocalized to smooth muscle cell actin in a differential pattern favoring medial distruction in the WT TAA compared with the KO TAA segments.

Conclusions— These results demonstrate that MMP-9 gene deletion attenuated TAA formation despite an increase in the zymographic levels of MMP-2. These unique findings suggest that an interaction between these 2 MMPs is necessary to facilitate TAA progression.

Key Words: aneurysm • aorta • thorax • MMP-9 • MMP-2