Effects of deletion of the matrix metalloproteinase 9 gene on development of murine thoracic aortic aneurysms.
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.


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.
Ikonomidis
John S
JS
Division of Cardiothoracic Surgery, Medical University of South Carolina, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC, USA. ikonomij@musc.edu
Barbour
John R
JR
Amani
Zainab
Z
Stroud
Robert E
RE
Herron
Amanda R
AR
McClister
David M
DM
Camens
Sarah E
SE
Lindsey
Merry L
ML
Mukherjee
Rupak
R
Spinale
Francis G
FG
D000199:Actins / Q000032:analysis; D000818:Animals; D017545:Aortic Aneurysm, Thoracic / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics; D002122:Calcium Chloride / Q000633:toxicity; D018450:Disease Progression; D004790:Enzyme Induction; D053508:Matrix Metalloproteinase 12; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008666:Metalloendopeptidases / Q000032:analysis; D051379:Mice; D018345:Mice, Knockout
D000199:Actins; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D053508:Matrix Metalloproteinase 12; D002122:Calcium Chloride