Published Online
on June 26, 2006

A more recent version of this article appeared on July 4, 2006

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Submitted on February 6, 2006
Revised on April 19, 2006
Accepted on May 1, 2006

Inflammation in Atherosclerosis. Visualizing Matrix Metalloproteinase Action in Macrophages In Vivo

Jun-o Deguchi MD, PhD, Masanori Aikawa MD, PhD, Ching-Hsuan Tung PhD, Elena Aikawa MD, PhD, Dong-Eog Kim MD, Vasilis Ntziachristos PhD, Ralph Weissleder MD, PhD, and Peter Libby MD^*

From the Donald W. Reynolds Cardiovascular Clinical Research Center, Harvard Medical School, Boston, Mass (J.D., M.A., C.T., E.A., D.K., R.W., P.L.); Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass (J.D., M.A., P.L.); and Center for Molecular Imaging Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, Mass (C.T., E.A., D.K., V.N., R.W.).

^* To whom correspondence should be addressed. E-mail: plibby{at}rics.bwh.harvard.edu.

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.

Key words: atherosclerosis • imaging • inflammation • macrophages • metalloproteinases

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