TY - JOUR
T1 - Evaluation of matrix metalloproteinases in atherosclerosis using a novel noninvasive imaging approach
AU - Lancelot, Eric
AU - Amirbekian, Vardan
AU - Brigger, Irène
AU - Raynaud, Jean Sébastien
AU - Ballet, Sébastien
AU - David, Christelle
AU - Rousseaux, Olivier
AU - Le Greneur, Soizic
AU - Port, Marc
AU - Lijnen, Henri R.
AU - Bruneval, Patrick
AU - Michel, Jean Baptiste
AU - Ouimet, Tanja
AU - Roques, Bernard
AU - Amirbekian, Smbat
AU - Hyafil, Fabien
AU - Vucic, Esad
AU - Aguinaldo, Juan Gilberto S.
AU - Corot, Claire
AU - Fayad, Zahi A.
PY - 2008/3/1
Y1 - 2008/3/1
N2 - Objective: Despite great advances in our knowledge, atherosclerosis continues to kill more people than any other disease in the Western world. This is because our means of identifying truly vulnerable patients is limited. Prediction of atherosclerotic plaque rupture may be addressed by MRI of activated matrix metalloproteinases (MMPs), a family of enzymes that have been implicated in the vulnerability of plaques prone to rupture. This study evaluated the ability of the novel gadolinium-based MRI contrast agent P947 to target MMPs in atherosclerotic plaques. Methods and Results: The affinity of P947 toward activated MMPs was demonstrated in vitro. The affinity and specificity of P947 toward matrix metalloproteinase (MMP)-rich plaques was evaluated both in vivo using ApoE -/- mice and ex vivo in hyperlipidemic rabbits. Gadolinium content quantification and MRI showed a preferential accumulation of P947 in atherosclerotic lesions compared with the nontargeted reference compound, Gd-DOTA. The ex vivo assay on rabbit plaques revealed a higher uptake of P947. Moreover, using human carotid artery endarterectomy specimens, P947 facilitated discrimination between histologically defined MMP-rich and MMP-poor plaques. An in vivo MRI investigation in mice revealed that P947 greatly improved the ability to visualize and delineate atherosclerotic plaques. Conclusions: P947 may be a useful tool for the detection and characterization of the MMP-rich atherosclerotic plaques.
AB - Objective: Despite great advances in our knowledge, atherosclerosis continues to kill more people than any other disease in the Western world. This is because our means of identifying truly vulnerable patients is limited. Prediction of atherosclerotic plaque rupture may be addressed by MRI of activated matrix metalloproteinases (MMPs), a family of enzymes that have been implicated in the vulnerability of plaques prone to rupture. This study evaluated the ability of the novel gadolinium-based MRI contrast agent P947 to target MMPs in atherosclerotic plaques. Methods and Results: The affinity of P947 toward activated MMPs was demonstrated in vitro. The affinity and specificity of P947 toward matrix metalloproteinase (MMP)-rich plaques was evaluated both in vivo using ApoE -/- mice and ex vivo in hyperlipidemic rabbits. Gadolinium content quantification and MRI showed a preferential accumulation of P947 in atherosclerotic lesions compared with the nontargeted reference compound, Gd-DOTA. The ex vivo assay on rabbit plaques revealed a higher uptake of P947. Moreover, using human carotid artery endarterectomy specimens, P947 facilitated discrimination between histologically defined MMP-rich and MMP-poor plaques. An in vivo MRI investigation in mice revealed that P947 greatly improved the ability to visualize and delineate atherosclerotic plaques. Conclusions: P947 may be a useful tool for the detection and characterization of the MMP-rich atherosclerotic plaques.
KW - Atherosclerosis
KW - Atherosclerotic plaque
KW - MRI
KW - Matrix metalloproteinases
KW - Molecular imaging
UR - http://www.scopus.com/inward/record.url?scp=40749151108&partnerID=8YFLogxK
U2 - 10.1161/ATVBAHA.107.149666
DO - 10.1161/ATVBAHA.107.149666
M3 - Article
C2 - 18258820
AN - SCOPUS:40749151108
SN - 1079-5642
VL - 28
SP - 425
EP - 432
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
IS - 3
ER -