In vivo evaluation of a new magnetic resonance imaging contrast agent (P947) to target matrix metalloproteinases in expanding experimental abdominal aortic aneurysms.
OBJECTIVE
Abdominal aortic aneurysm (AAA) rupture is a devastating event, and development of noninvasive methods to detect AAA at risk is needed. Matrix metalloproteinases (MMPs) play a major role in AAA growth and their subsequent rupture. This study was aimed to evaluate the ability of P947, a recently developed magnetic resonance imaging (MRI) contrast agent, to target MMPs in vivo in expanding experimental AAAs.


METHODS
AAAs were induced in Wistar rats (n = 18) by perfusion of a segment of the abdominal aorta with porcine elastase. After 5 or 6 days of elastase perfusion, when the aortic segment was expanding and showed inflammation with high MMP levels, rats were injected either with P947 (n = 6), P1135, a scramble form of P947 (n = 6), or with the reference contrast agent Gadolinium-DOTA (Gd-DOTA) (n = 3). Sham-operated rats (n = 3) were injected with P947 as controls. Imaging was performed on the animals using a 1.5T MRI scanner before and at different times after injection of contrast agents (100 μmol/kg). Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) gelatin zymography of culture media conditioned by incubation with perfused aortic segment or control TA from elastase-perfused rats (n = 3) was performed to determine levels of MMP2 and MMP9. In addition, in situ gelatin zymography was used to localize these active MMPs on frozen histologic sections.


RESULTS
The normalized signal enhancement determined on MRI images was higher in the perfused aortic segment of rats injected with P947 (162%) than in rats injected with P1135 (100%) or Gd-DOTA (117%) (P < 0.01 using the Friedman test) from 5 to 125 minutes after injection. The area of contrast enhancement on MRI images colocalized with the fluorescence generated by MMPs in the AAA inflammatory area, as detected by in situ zymography on histologic sections.


CONCLUSIONS
Our data showed that MRI using P947 allows detection of MMP activity within the inflammatory wall of experimental AAAs, thus representing a potential noninvasive method to detect AAAs with a high risk of rupture.
Bazeli
Romain
R
Department of Radiology, Bichat Hospital, Paris, France.
Coutard
Michèle
M
Duport
Benjamin Daumas
BD
Lancelot
Eric
E
Corot
Claire
C
Laissy
Jean-Pierre
JP
Letourneur
Didier
D
Michel
Jean-Baptiste
JB
Serfaty
Jean-Michel
JM
D000818:Animals; D001012:Aorta, Abdominal / Q000000981:diagnostic imaging / Q000201:enzymology; D017544:Aortic Aneurysm, Abdominal / Q000000981:diagnostic imaging* / Q000201:enzymology; D003287:Contrast Media; D004195:Disease Models, Animal; D006571:Heterocyclic Compounds; D008279:Magnetic Resonance Imaging; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D057054:Molecular Imaging; D009942:Organometallic Compounds; D010196:Pancreatic Elastase / Q000378:metabolism; D011877:Radionuclide Imaging; D051381:Rats; D017208:Rats, Wistar; D018709:Statistics, Nonparametric
D003287:Contrast Media; D006571:Heterocyclic Compounds; D009942:Organometallic Compounds; C050823:gadolinium 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetate; D010196:Pancreatic Elastase; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9