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Published on: November 3, 2015
Inflammation in atherosclerosis: visualizing matrix metalloproteinase action in macrophages in vivo
Jun-o Deguchi1, Masanori Aikawa, Ching-Hsuan Tung
1Donald W. Reynolds Cardiovascular Clinical Research Center, Harvard Medical School, Boston, Massachusetts, USA.
Background:
Matrix metalloproteinases (MMPs) in inflamed atherosclerotic plaques may contribute to extracellular matrix remodeling and the onset of acute thrombotic complications.
Methods And Results:
To test the hypothesis that optical molecular imaging with the use of an activatable near-infrared fluorescence (NIRF) probe can detect enzymatic action of MMP in atherosclerotic plaques, we used a NIRF substrate for gelatinases (MMP-2/gelatinase-A and MMP-9/gelatinase-B) in apolipoprotein E-deficient (apoE-/-) mice that consumed a high-cholesterol diet for 12 weeks and age-matched apoE+/+ mice as control. The aortas of apoE-/- mice at 24 hours after probe yielded intense NIRF signals, as detected by NIRF reflectance ex vivo, compared with negligible signals in aortas of apoE+/+ mice with/without probe administration or atherosclerotic apoE-/- aortas without probe. Gelatinase inhibitor treatment abolished NIRF signals in apoE-/- mouse aortas ex vivo. Sites of gelatinase activity visualized by NIRF colocalized with macrophage accumulation, immunoreactive MMP-2 and MMP-9, and gelatinolytic activity detected by in situ zymography. Furthermore, fluorescence molecular tomography indicated in vivo that atherosclerotic aortas of apoE-/- mice produced NIRF signals for gelatinase action, whereas aortas of apoE+/+ mice injected with the probe or apoE-/- aortas with no probe exhibited negligible NIRF signals.
Conclusions:
These results suggest the feasibility of noninvasively imaging the enzymatic action of MMPs in vivo, an approach that may gauge inflammatory foci in atherosclerosis, assess cardiovascular risk, and evaluate the effects of therapeutic interventions.
Insights
Optical molecular imaging effectively detects matrix metalloproteinase (MMP) activity in atherosclerotic plaques. This approach visualizes gelatinase action in vivo, aiding in assessing cardiovascular risk and therapeutic efficacy.
Area of Science:
- Biomedical Imaging
- Molecular Biology
- Cardiovascular Research
Background:
- Matrix metalloproteinases (MMPs) play a role in atherosclerotic plaque remodeling and thrombotic events.
- Inflamed atherosclerotic plaques are characterized by MMP activity.
Purpose of the Study:
- To evaluate optical molecular imaging using a near-infrared fluorescence (NIRF) probe for detecting MMP enzymatic action in atherosclerosis.
- To assess the feasibility of noninvasive in vivo imaging of MMP activity.
Main Methods:
- Apolipoprotein E-deficient (apoE-/-) mice on a high-cholesterol diet were used to model atherosclerosis.
- A NIRF substrate for gelatinases (MMP-2/MMP-9) was administered, and NIRF signals were detected ex vivo and in vivo.
- In situ zymography and immunohistochemistry were used to confirm gelatinase activity and MMP presence.
Main Results:
- Atherosclerotic aortas in apoE-/- mice showed intense NIRF signals, indicating gelatinase activity, unlike control mice.
- NIRF signal localization correlated with macrophage accumulation and MMP-2/MMP-9 expression.
- In vivo fluorescence molecular tomography confirmed the detection of gelatinase action in atherosclerotic aortas.
Conclusions:
- Noninvasive in vivo imaging of MMP enzymatic action in atherosclerosis is feasible.
- This imaging approach can help gauge inflammatory foci and assess cardiovascular risk.
- The method holds potential for evaluating the efficacy of therapeutic interventions in atherosclerosis.
