Effects of deletion of the tissue inhibitor of matrix metalloproteinases-1 gene on the progression of murine thoracic aortic aneurysms.
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.


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.
Ikonomidis
John S
JS
Assistant Professor of Surgery, Division of Cardiothoracic Surgery, Medical University of South Carolina, Suite 409 CSB, 96 Jonathan Lucas Street, Charleston, SC 29425, USA. ikonomij@musc.edu
Gibson
William C
WC
Butler
Jessica E
JE
McClister
David M
DM
Sweterlitsch
Sarah E
SE
Thompson
Robert P
RP
Mukherjee
Rupak
R
Spinale
Francis G
FG
D000818:Animals; D017545:Aortic Aneurysm, Thoracic / Q000201:enzymology / Q000473:pathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D017353:Gene Deletion; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D020782:Matrix Metalloproteinases / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D010641:Phenotype; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology
D019715:Tissue Inhibitor of Metalloproteinase-1; D020782:Matrix Metalloproteinases; D020780:Matrix Metalloproteinase 9