Evaluation of matrix metalloproteinases in atherosclerosis using a novel noninvasive imaging approach

Eric Lancelot, Vardan Amirbekian, Irène Brigger, Jean Sébastien Raynaud, Sébastien Ballet, Christelle David, Olivier Rousseaux, Soizic Le Greneur, Marc Port, Henri R. Lijnen, Patrick Bruneval, Jean Baptiste Michel, Tanja Ouimet, Bernard Roques, Smbat Amirbekian, Fabien Hyafil, Esad Vucic, Juan Gilberto S. Aguinaldo, Claire Corot, Zahi A. Fayad

Research output: Contribution to journalArticlepeer-review

124 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)425-432
Number of pages8
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume28
Issue number3
DOIs
StatePublished - 1 Mar 2008

Keywords

  • Atherosclerosis
  • Atherosclerotic plaque
  • MRI
  • Matrix metalloproteinases
  • Molecular imaging

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