This Article Full Text Full Text (PDF) All Versions of this Article: 114/1/55    most recent CIRCULATIONAHA.106.619056v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Deguchi, J.-o Articles by Libby, P. Search for Related Content PubMed PubMed Citation Articles by Deguchi, J.-o Articles by Libby, P. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Related Collections Cardiovascular imaging agents/Techniques Mechanism of atherosclerosis/growth factors Other Vascular biology Animal models of human disease Pathophysiology Genetically altered mice Imaging

(Circulation. 2006;114:55-62.)
© 2006 American Heart Association, Inc.

Vascular Medicine

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; 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.).

Correspondence to Peter Libby, MD, or Masanori Aikawa, MD, PhD, Brigham and Women’s Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, NRB 741, Boston, MA 02115. E-mail plibby{at}rics.bwh.harvard.edu or maikawa@rics.bwh.harvard.edu

Received February 6, 2006; revision received April 19, 2006; accepted May 1, 2006.

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.

---

 

CLINICAL PERSPECTIVE

This article has been cited by other articles:

				C. Franco, G. Hou, P. J. Ahmad, E. Y.K. Fu, L. Koh, W. F. Vogel, and M. P. Bendeck Discoidin Domain Receptor 1 (Ddr1) Deletion Decreases Atherosclerosis by Accelerating Matrix Accumulation and Reducing Inflammation in Low-Density Lipoprotein Receptor-Deficient Mice Circ. Res., May 23, 2008; 102(10): 1202 - 1211. [Abstract] [Full Text] [PDF]

				V. Bourlier, A. Zakaroff-Girard, A. Miranville, S. De Barros, M. Maumus, C. Sengenes, J. Galitzky, M. Lafontan, F. Karpe, K.N. Frayn, et al. Remodeling Phenotype of Human Subcutaneous Adipose Tissue Macrophages Circulation, February 12, 2008; 117(6): 806 - 815. [Abstract] [Full Text] [PDF]

				E. Aikawa, M. Nahrendorf, J.-L. Figueiredo, F. K. Swirski, T. Shtatland, R. H. Kohler, F. A. Jaffer, M. Aikawa, and R. Weissleder Osteogenesis Associates With Inflammation in Early-Stage Atherosclerosis Evaluated by Molecular Imaging In Vivo Circulation, December 11, 2007; 116(24): 2841 - 2850. [Abstract] [Full Text] [PDF]

				P. K. Cheruvu, A. V. Finn, C. Gardner, J. Caplan, J. Goldstein, G. W. Stone, R. Virmani, and J. E. Muller Frequency and Distribution of Thin-Cap Fibroatheroma and Ruptured Plaques in Human Coronary Arteries: A Pathologic Study J. Am. Coll. Cardiol., September 4, 2007; 50(10): 940 - 949. [Abstract] [Full Text] [PDF]

				J. Ohayon, O. Dubreuil, P. Tracqui, S. Le Floc'h, G. Rioufol, L. Chalabreysse, F. Thivolet, R. I. Pettigrew, and G. Finet Influence of residual stress/strain on the biomechanical stability of vulnerable coronary plaques: potential impact for evaluating the risk of plaque rupture Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1987 - H1996. [Abstract] [Full Text] [PDF]

				F. A. Jaffer, P. Libby, and R. Weissleder Molecular Imaging of Cardiovascular Disease Circulation, August 28, 2007; 116(9): 1052 - 1061. [Full Text] [PDF]

				B. A. Kaufmann, J. M. Sanders, C. Davis, A. Xie, P. Aldred, I. J. Sarembock, and J. R. Lindner Molecular Imaging of Inflammation in Atherosclerosis With Targeted Ultrasound Detection of Vascular Cell Adhesion Molecule-1 Circulation, July 17, 2007; 116(3): 276 - 284. [Abstract] [Full Text] [PDF]

				H.-J. Cho, J. H. Kang, J.-Y. Kwak, T.-S. Lee, I.-S. Lee, N. G. Park, H. Nakajima, J. Magae, and Y.-C. Chang Ascofuranone suppresses PMA-mediated matrix metalloproteinase-9 gene activation through the Ras/Raf/MEK/ERK- and Ap1-dependent mechanisms Carcinogenesis, May 1, 2007; 28(5): 1104 - 1110. [Abstract] [Full Text] [PDF]

				J. Sanz, P. R. Moreno, and V. Fuster The Year in Atherothrombosis J. Am. Coll. Cardiol., April 24, 2007; 49(16): 1740 - 1749. [Full Text] [PDF]

				Y. Hama, Y. Urano, Y. Koyama, P. L. Choyke, and H. Kobayashi Activatable Fluorescent Molecular Imaging of Peritoneal Metastases following Pretargeting with a Biotinylated Monoclonal Antibody Cancer Res., April 15, 2007; 67(8): 3809 - 3817. [Abstract] [Full Text] [PDF]

				D. E. Sosnovik, M. Nahrendorf, N. Deliolanis, M. Novikov, E. Aikawa, L. Josephson, A. Rosenzweig, R. Weissleder, and V. Ntziachristos Fluorescence Tomography and Magnetic Resonance Imaging of Myocardial Macrophage Infiltration in Infarcted Myocardium In Vivo Circulation, March 20, 2007; 115(11): 1384 - 1391. [Abstract] [Full Text] [PDF]

				E. Aikawa, M. Nahrendorf, D. Sosnovik, V. M. Lok, F. A. Jaffer, M. Aikawa, and R. Weissleder Multimodality Molecular Imaging Identifies Proteolytic and Osteogenic Activities in Early Aortic Valve Disease Circulation, January 23, 2007; 115(3): 377 - 386. [Abstract] [Full Text] [PDF]

				P. Libby Perplexity of Plaque Proteinases Arterioscler. Thromb. Vasc. Biol., October 1, 2006; 26(10): 2181 - 2182. [Full Text] [PDF]