CLINICAL RESEARCH: CARDIAC IMAGING
Molecular Imaging of Matrix Metalloproteinase in Atherosclerotic LesionsResolution With Dietary Modification and Statin Therapy
Shinichiro Fujimoto, MD, PhD*,
Dagmar Hartung, MD*,
Satoru Ohshima, MD, PhD*,
D. Scott Edwards, PhD ,
Jun Zhou, MD*,
Padmaja Yalamanchili, PhD,
Michael Azure, PhD,
Ai Fujimoto, MD, PhD*,
Satoshi Isobe, MD, PhD*,
Yuji Matsumoto, MD, PhD*,
Hendricus Boersma, PharmD, PhD ,
Nathan Wong, PhD*,
Junichi Yamazaki, MD ,
Navneet Narula, MD*,
Artiom Petrov, PhD*,* and
Jagat Narula, MD, PhD, FACC*
* University of California, Irvine School of Medicine, Irvine, California
Bristol-Myers Squibb, Medical Imaging, North Billerica, Massachusetts
University Medical Center, Groningen, the Netherlands
Toho University School of Medicine, Ohmori Hospital, Tokyo, Japan
Manuscript received January 11, 2008;
revised manuscript received August 12, 2008,
accepted August 12, 2008.
* Reprint requests and correspondence: Dr. Artiom Petrov, Division of Cardiology, University of California, Irvine, Medical Science Building I, Room C-116, UCI Main Campus, Irvine, California 92697 (Email: adpetrov{at}uci.edu).
Objectives: This study sought to evaluate the feasibility of noninvasive detection of matrix metalloproteinase (MMP) activity in experimental atherosclerosis using technetium-99m–labeled broad matrix metalloproteinase inhibitor (MPI) and to determine the effect of dietary modification and statin treatment on MMP activity.
Background: The MMP activity in atherosclerotic lesions contributes to the vulnerability of atherosclerotic plaques to rupture.
Methods: Atherosclerosis was produced in 34 New Zealand White rabbits by balloon de-endotheliazation of the abdominal aorta and a high-cholesterol diet. In addition, 12 unmanipulated rabbits were used as controls and 3 for blood clearance characteristics. In vivo micro–single-photon emission computed tomography (SPECT) imaging was performed after radiolabeled MPI administration. Subsequently, aortas were explanted to quantitatively measure percent injected dose per gram (%ID/g) MPI uptake. Histological and immunohistochemical characterization was performed and the extent of MMP activity was determined by gel zymography or enzyme-linked immunosorbent assays.
Results: The MPI uptake in atherosclerotic lesions (n = 18) was clearly visualized by micro-SPECT imaging; MPI uptake was markedly reduced by administration of unlabeled MPI before the radiotracer (n = 4). The MPI uptake was also significantly reduced after diet withdrawal (n = 6) and fluvastatin treatment (n = 6); no uptake was observed in normal control rabbits (n = 12). The %ID/g MPI uptake (0.10 ± 0.03%) in the atherosclerotic lesions was significantly higher than the uptake in control aorta (0.016 ± 0.004%, p < 0.0001). Uptake in fluvastatin (0.056 ± 0.011%, p < 0.0005) and diet withdrawal groups (0.043 ± 0.011%, p < 0.0001) was lower than the untreated group. The MPI uptake correlated with immunohistochemically verified macrophage infiltration (r = 0.643, p < 0.0001), and MMP-2 (r = 0.542, p < 0.0001) or MMP-9 (r = 0.578, p < 0.0001) expression in plaques.
Conclusions: The present data show the feasibility of noninvasive detection of MMP activity in atherosclerotic plaques, and confirm that dietary modification and statin therapy reduce MMP activity.
Key Words: matrix metalloproteinase • molecular imaging • atherosclerosis • HMG coenzyme reductase inhibitor
|
Abbreviations and Acronyms
| | %ID/g = percent total injected dose per gram of tissue | | CT = computed tomography | | HC = high cholesterol | | MMP = matrix metalloproteinase | | MPI = matrix metalloproteinase inhibitor | | NZW = New Zealand White | | PBS = phosphate-buffered saline | | SMC = smooth muscle cell | | SPECT = single-photon emission computed tomography |
|
Related Article
-
Inside This Issue of JACC
J. Am. Coll. Cardiol. 2008 52: A40.
[Full Text]
[PDF]
This article has been cited by other articles:
|
|
|
|
 
T. A. Hope and M. D. Hope
Improved Risk Assessment for Abdominal Aortic Aneurysm Rupture: Off-the-Wall Imaging
J. Am. Coll. Cardiol.,
December 6, 2011;
58(24):
2531 - 2532.
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Razavian, R. Marfatia, H. Mongue-Din, S. Tavakoli, A. J. Sinusas, J. Zhang, L. Nie, and M. M. Sadeghi
Integrin-Targeted Imaging of Inflammation in Vascular Remodeling
Arterioscler Thromb Vasc Biol,
December 1, 2011;
31(12):
2820 - 2826.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Razavian, S. Tavakoli, J. Zhang, L. Nie, L. W. Dobrucki, A. J. Sinusas, M. Azure, S. Robinson, and M. M. Sadeghi
Atherosclerosis Plaque Heterogeneity and Response to Therapy Detected by In Vivo Molecular Imaging of Matrix Metalloproteinase Activation
J. Nucl. Med.,
November 1, 2011;
52(11):
1795 - 1802.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. L. Grodin, T. M. Powell-Wiley, C. R. Ayers, D. S. Kumar, A. Rohatgi, A. Khera, D. K. McGuire, J. A. de Lemos, and S. R. Das
Circulating levels of matrix metalloproteinase-9 and abdominal aortic pathology: From the Dallas Heart Study
Vascular Medicine,
October 1, 2011;
16(5):
339 - 345.
[Abstract]
[PDF]
|
|
|
|
|
|
|
F. Hyafil, E. Vucic, J.-C. Cornily, R. Sharma, V. Amirbekian, F. Blackwell, E. Lancelot, C. Corot, V. Fuster, Z. S. Galis, et al.
Monitoring of arterial wall remodelling in atherosclerotic rabbits with a magnetic resonance imaging contrast agent binding to matrix metalloproteinases
Eur. Heart J.,
June 2, 2011;
32(12):
1561 - 1571.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Vancraeynest, A. Pasquet, V. Roelants, B. L. Gerber, and J.-L. J. Vanoverschelde
Imaging the Vulnerable Plaque
J. Am. Coll. Cardiol.,
May 17, 2011;
57(20):
1961 - 1979.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.-C. Tardif, F. Lesage, F. Harel, P. Romeo, and J. Pressacco
Imaging Biomarkers in Atherosclerosis Trials
Circ Cardiovasc Imaging,
May 1, 2011;
4(3):
319 - 333.
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Tavakoli, M. Razavian, J. Zhang, L. Nie, R. Marfatia, L. W. Dobrucki, A. J. Sinusas, S. Robinson, D. S. Edwards, and M. M. Sadeghi
Matrix Metalloproteinase Activation Predicts Amelioration of Remodeling After Dietary Modification in Injured Arteries
Arterioscler Thromb Vasc Biol,
January 1, 2011;
31(1):
102 - 109.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. A. Osborn and F. A. Jaffer
The Year in Molecular Imaging
J. Am. Coll. Cardiol. Img.,
November 1, 2010;
3(11):
1181 - 1195.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Inoue, S. Motoyama, M. Sarai, T. Sato, H. Harigaya, T. Hara, Y. Sanda, H. Anno, T. Kondo, N. D. Wong, et al.
Serial Coronary CT Angiography-Verified Changes in Plaque Characteristics as an End Point: Evaluation of Effect of Statin Intervention
J. Am. Coll. Cardiol. Img.,
July 1, 2010;
3(7):
691 - 698.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Razavian, J. Zhang, L. Nie, S. Tavakoli, N. Razavian, L. W. Dobrucki, A. J. Sinusas, D. S. Edwards, M. Azure, and M. M. Sadeghi
Molecular Imaging of Matrix Metalloproteinase Activation to Predict Murine Aneurysm Expansion In Vivo
J. Nucl. Med.,
July 1, 2010;
51(7):
1107 - 1115.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Schafers, O. Schober, and S. Hermann
Matrix-Metalloproteinases as Imaging Targets for Inflammatory Activity in Atherosclerotic Plaques
J. Nucl. Med.,
May 1, 2010;
51(5):
663 - 666.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. M. Sadeghi, D. K. Glover, G. M. Lanza, Z. A. Fayad, and L. L. Johnson
Imaging Atherosclerosis and Vulnerable Plaque
J. Nucl. Med.,
May 1, 2010;
51(Supplement_1):
51S - 65S.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Sanz, P. R. Moreno, and V. Fuster
The Year in Atherothrombosis
J. Am. Coll. Cardiol.,
April 6, 2010;
55(14):
1487 - 1498.
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Ohshima, S. Fujimoto, A. Petrov, H. Nakagami, N. Haider, J. Zhou, N. Tahara, M. K. Osako, A. Fujimoto, J. Zhu, et al.
Effect of an Antimicrobial Agent on Atherosclerotic Plaques: Assessment of Metalloproteinase Activity by Molecular Imaging
J. Am. Coll. Cardiol.,
March 23, 2010;
55(12):
1240 - 1249.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Ohshima, A. Petrov, S. Fujimoto, J. Zhou, M. Azure, D. S. Edwards, T. Murohara, N. Narula, S. Tsimikas, and J. Narula
Molecular Imaging of Matrix Metalloproteinase Expression in Atherosclerotic Plaques of Mice Deficient in Apolipoprotein E or Low-Density-Lipoprotein Receptor
J. Nucl. Med.,
April 1, 2009;
50(4):
612 - 617.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
