Early MT-1 MMP expression following elastase exposure is associated with increased cleaved MMP-2 activity in experimental rodent aortic aneurysms.
OBJECTIVE
The objective of this study was to determine the significance of membrane type 1 matrix metalloproteinase (MT1-MMP) activation of MMP-2 in experimental abdominal aortic aneurysms.


METHODS
Rat aortas were perfused with either saline as a control or elastase, and harvested on 2, 4, or 7 days after perfusion (n = 5 per treatment group/day). Aortic MT1-MMP and MMP-2 expression and protein were determined by real time polymerase chain reaction and Western blotting, respectively. Aortic explants were used to measure MMP-2 activity by zymography. Rat aortic smooth muscle cells in vitro were exposed to increasing doses of elastase and analyzed for MT-1 MMP expression.


RESULTS
Aneurysms formed in 80% of the elastase-perfused aortas at 7 days, whereas none formed in the saline-perfused aortas. Significantly increased MT1-MMP expression was observed only on day 4, when levels were 6.5-fold higher in elastase-perfused aortas compared with saline-perfused aortas (P < .01). By day 7, MT1-MMP protein was present only in the elastase-perfused aortas (P = .02). By immunohistochemistry, MT1-MMP was detectable only in the elastase-perfused group at day 7. Cleaved MMP-2 activity (P = .045) was increased in elastase-perfused aortas compared with saline perfused aortas at day 7. In rat aortic smooth muscle cells, MT-1 MMP expression increased in response to elastase (P = .02).


CONCLUSIONS
The rodent aortic aneurysm model exhibits upregulation of MT1-MMP expression and protein with subsequent increased conversion of MMP-2 from the latent to the cleaved form.
Sinha
Indranil
I
Jobst Vascular Research Laboratories, Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI 48109-0329, USA.
Hannawa
Kevin K
KK
Eliason
Jonathan L
JL
Ailawadi
Gorav
G
Deogracias
Michael P
MP
Bethi
Siddharth
S
Ford
John W
JW
Roelofs
Karen J
KJ
Grigoryants
Vladimir
V
Henke
Peter K
PK
Stanley
James C
JC
Upchurch
Gilbert R
GR
D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000201:enzymology*; D005786:Gene Expression Regulation; D007150:Immunohistochemistry; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000032:analysis*; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000235:genetics*; D010196:Pancreatic Elastase / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D010196:Pancreatic Elastase; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2