Dual molecular imaging for targeting metalloproteinase activity and apoptosis in atherosclerosis: molecular imaging
Nezam Haider1, Dagmar Hartung, Shinichiro Fujimoto
1Department of Cardiology, Irvine School of Medicine, University of California, C116 Med Sci I, Irvine, CA 92697, USA.
Background:
Macrophage apoptosis and MMP activity contribute to vulnerability of atherosclerotic plaques to rupture. By employing molecular imaging techniques, we investigated if apoptosis and MMP release are interlinked.
Methods:
Atherosclerosis was produced in rabbits receiving high-cholesterol diet (HC), who underwent dual radionuclide imaging with (99m)Tc-labeled matrix metalloproteinase inhibitor (MPI) and (111)In-labeled annexin A5 (AA5) using micro-SPECT/CT. %ID/g MPI and AA5 uptake was measured, followed by histological characterization. Unmanipulated animals were used as disease controls. Correlation between MPI and AA5 uptake was undertaken and relationship confirmed in culture study of activated THP-1 monocytes.
Results:
MPI and AA5 uptake was best visualized in HC diet animals (n = 6) and reduced significantly after fluvastatin treatment (n = 4) or diet withdrawal (n = 3). %ID/g MPI (.087 +/- .018%) and AA5 (.03 +/- .01%) uptake was higher in HC than control (n = 6) animals (.014 +/- .004%, P < .0001; .0007 +/- .0002%, P < .0001), and reduced substantially after diet or statin intervention. There was a significant correlation between MPI and AA5 uptake (r = .62, P < .0001), both correlated with pathologically verified MMP-9 activity, macrophage content, and TUNEL staining. In vitro studies demonstrated MMP-9 release in culture medium from apoptotic THP-1 monocytes.
Conclusions:
The present study suggests that apoptosis and MMP are interrelated in atherosclerotic lesions and the targeting of more than one molecular candidate is feasible by molecular imaging.
Insights
Molecular imaging reveals apoptosis and matrix metalloproteinase (MMP) activity are linked in vulnerable atherosclerotic plaques. This study demonstrates dual-tracer imaging can target both molecular culprits simultaneously.
Area of Science:
- Cardiovascular Research
- Molecular Imaging
- Biomedical Engineering
Background:
- Macrophage apoptosis and matrix metalloproteinase (MMP) activity are key factors in atherosclerotic plaque vulnerability and rupture.
- Understanding the interplay between apoptosis and MMP release is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the interrelationship between macrophage apoptosis and MMP release in atherosclerotic plaques using molecular imaging.
- To assess the feasibility of simultaneously targeting both apoptosis and MMP activity.
Main Methods:
- Dual radionuclide imaging with (99m)Tc-labeled matrix metalloproteinase inhibitor (MPI) and (111)In-labeled annexin A5 (AA5) was performed using micro-SPECT/CT in rabbits with diet-induced atherosclerosis.
- Uptake of MPI and AA5 was quantified and correlated with histological findings, including MMP-9 activity, macrophage content, and TUNEL staining.
- In vitro studies using activated THP-1 monocytes confirmed MMP-9 release from apoptotic cells.
Main Results:
- MPI and AA5 uptake were significantly higher in atherosclerotic rabbits compared to controls, indicating increased apoptosis and MMP activity.
- Uptake of both tracers decreased significantly after fluvastatin treatment or diet withdrawal.
- A significant positive correlation was observed between MPI and AA5 uptake, and both correlated with pathological markers of plaque instability.
- In vitro experiments confirmed MMP-9 release from apoptotic monocytes.
Conclusions:
- Apoptosis and MMP activity are interrelated in atherosclerotic lesions.
- Molecular imaging can effectively target and visualize both apoptosis and MMP activity simultaneously.
- This dual-targeting approach holds promise for assessing plaque vulnerability and guiding therapeutic interventions.
