1. Selective Imaging of Matrix Metalloproteinase-13 to Detect Extracellular Matrix Remodeling in Atherosclerotic Lesions.
- Author
-
Buchler, Ariel, Munch, Maxime, Farber, Gedaliah, Zhao, Xiaoling, Al-Haddad, Rami, Farber, Eadan, and Rotstein, Benjamin H.
- Subjects
EXTRACELLULAR matrix ,STAINS & staining (Microscopy) ,IMAGE analysis ,ATHEROSCLEROTIC plaque ,MATRIX metalloproteinases ,TRANSLOCATOR proteins ,BIOMARKERS ,IN vivo studies ,INFLAMMATION ,ANIMAL experimentation ,CELL receptors ,ATHEROSCLEROSIS ,EXTRACELLULAR space ,SENSITIVITY & specificity (Statistics) ,MOLECULAR structure ,EMISSION-computed tomography ,MICE - Abstract
Purpose: Overexpression and activation of matrix metalloproteinase-13 (MMP-13) within atheroma increases susceptibility to plaque rupture, a major cause of severe cardiovascular complications. In comparison to pan-MMP targeting [
18 F]BR-351, we evaluated the potential for [18 F]FMBP, a selective PET radiotracer for MMP-13, to detect extracellular matrix (ECM) remodeling in vascular plaques possessing markers of inflammation. Procedures: [18 F]FMBP and [18 F]BR-351 were initially assessed in vitro by incubation with en face aortae from 8 month-old atherogenic ApoE−/− mice. Ex vivo biodistributions, plasma metabolite analyses, and ex vivo autoradiography were analogously performed 30 min after intravenous radiotracer administration in age-matched C57Bl/6 and ApoE−/− mice under baseline or homologous blocking conditions. En face aortae were subsequently stained with Oil Red O (ORO), sectioned, and subject to immunofluorescence staining for Mac-2 and MMP-13. Results: High-resolution autoradiographic image analysis demonstrated target specificity and regional concordance to lipid-rich lesions. Biodistribution studies revealed hepatobiliary excretion, low accumulation of radioactivity in non-excretory organs, and few differences between strains and conditions in non-target organs. Plasma metabolite analyses uncovered that [18 F]FMBP exhibited excellent in vivo stability (≥74% intact) while [18 F]BR-351 was extensively metabolized (≤37% intact). Ex vivo autoradiography and histology of en face aortae revealed that [18 F]FMBP, relative to [18 F]BR-351, exhibited 2.9-fold greater lesion uptake, substantial specific binding (68%), and improved sensitivity to atherosclerotic tissue (2.9-fold vs 2.1-fold). Immunofluorescent staining of aortic en face cross sections demonstrated elevated Mac-2 and MMP-13-positive areas within atherosclerotic lesions identified by [18 F]FMBP ex vivo autoradiography. Conclusions: While both radiotracers successfully identified atherosclerotic plaques, [18 F]FMBP showed superior specificity and sensitivity for lesions possessing features of destructive plaque remodeling. The detection of ECM remodeling by selective targeting of MMP-13 may enable characterization of high-risk atherosclerosis featuring elevated collagenase activity. [ABSTRACT FROM AUTHOR]- Published
- 2022
- Full Text
- View/download PDF