Abstract:
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.
journal_name
Circulationjournal_title
Circulationauthors
Deguchi JO,Aikawa M,Tung CH,Aikawa E,Kim DE,Ntziachristos V,Weissleder R,Libby Pdoi
10.1161/CIRCULATIONAHA.106.619056subject
Has Abstractpub_date
2006-07-04 00:00:00pages
55-62issue
1eissn
0009-7322issn
1524-4539pii
CIRCULATIONAHA.106.619056journal_volume
114pub_type
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