doi: 10.1161/CIRCIMAGING.108.828152
Editorials |
"Feeling the RAGE" in the Atherosclerotic Vessel Wall
From the Translational and Molecular Imaging Institute, Mount Sinai School of Medicine, New York, NY.
Correspondence to Zahi A. Fayad, PhD, Translational and Molecular Imaging Institute, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1234, New York, NY 10029. Email zahi.fayad{at}mssm.edu
Key Words: arteriosclerosis • imaging • plaque • radioisotopes
Molecular imaging can be broadly defined as the in vivo characterization and measurement of biological processes at the cellular and molecular level.1 In this context, the noninvasive detection of molecular signatures of disease entities using molecular imaging holds great promise for the development of personalized medicine and drug development.2,3 One of the first clinically validated and useful tomographic molecular imaging techniques was implemented in the field of oncology, with the use of [18F]fluoro-2-deoxy-D-glucose (FDG) positron-emission tomography (PET) and, more recently, that of FDG PET/computed tomography (CT) in cancer diagnosis and management. Although traditionally the primary focus has been on cancer biology, molecular imaging techniques have been expanded into the field of cardiovascular disease for a wide variety of clinically important entities.4 Especially, the molecular imaging of atherosclerosis has gained much attention.
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One major focus of molecular imaging of atherosclerosis is the detection of vessel wall inflammation and associated atherosclerotic plaque vulnerability. Conventional imaging modalities, such as x-ray angiography, can precisely define the artery lumen but do not provide any additional information about plaque composition or its grade of inflammation and associated risk of rupture. The accurate determination of the plaque inflammatory state might permit more precise patient risk stratification, better monitoring of therapy response, and rapid evaluation of novel therapeutic drugs by serial imaging. Historically, radionuclide conjugated antibodies were one of the earliest methods applied for the detection of biologically relevant molecules or epitopes in molecular imaging of cardiovascular disease.5 These initial approaches were refined by the use of small, high-affinity peptides as targeting ligands conjugated to different reporters. High-affinity peptides were obtained for this application by biological screens and, more recently, with phage display.6 Nanoparticular approaches, which allow molecular imaging using multiple imaging modalities, represent one of the latest and most exciting developments in this field.7
Several clinical imaging techniques have been applied for the purpose of molecular imaging of atherosclerosis, including ultrasound, CT, MRI, PET/CT, and single-photon emission computed tomography (SPECT)/CT.8,9 These imaging techniques are aimed at different targets of inflammation and vulnerability by using different targeting ligands. Because of their important role at all stages of atherosclerosis and plaque vulnerability, macrophages have been an important target for molecular images of atherosclerosis. A multitude of imaging approaches have been applied for this purpose, and more advanced in this respect is the assessment of metabolic activity (ie, glycolysis) in the vessel wall by using FDG-PET/CT and detection of macrophages with iron oxide nanoparticles.9 Other important targets within the vessel wall include apoptosis (targeting phosphatidylserine), the vascular cell adhesion molecules (targeting vascular cell adhesion molecule 1 and selectins), neovessels (targeting the integrin-
vβ3), oxidized low-density lipoproteins, thrombi, and protease activity of degrading enzymes (matrix metalloproteinases and cathepsins) within the atherosclerotic plaque.10
The ability to detect an important target in the vessel wall implicated in atherosclerosis progression and, potentially, in vulnerability—the receptor of advanced glycation end products (RAGE)—has been missing to date. In this issue of Circulation: Cardiovascular Imaging, Tekabe et al11 demonstrate the noninvasive detection of RAGE in the atherosclerotic vessel wall of hypercholesterolemic mice. This is an exciting development that adds an important marker of atherosclerotic disease that can now be assessed noninvasively.
RAGE is a member of the immunoglobulin superfamily of cell-surface receptors. The ligand–RAGE axis has emerged as a central mechanism linked to vascular injury and atherosclerosis in diabetes and euglycemia.12 RAGE possesses a diverse range of ligands, and in the vessel wall, 3 are of particular importance: advanced glycation end products, S100/calgranulins, and high-mobility group box 1/amphoterin. In atherosclerosis, the ligands for RAGE are expressed in both diabetic and nondiabetic conditions, although to a higher degree in diabetes. RAGE itself is expressed in all cell types pertinent for the development and progression of atherosclerotic plaque (ie, endothelial cells, smooth muscle cells, monocytes/macrophages, and T and B lymphocytes). The interaction of RAGE ligands with RAGE in inflammatory cells and vascular cells leads to the activation of transcription factors, such as nuclear factor-
B, which leads to the upregulation of inflammatory cytokines, vascular adhesion molecules, matrix metalloproteinases, and tissue factor.13 Sustained activation of RAGE through its ligands leads to chronic cellular activation, promoting vascular inflammation and endothelial dysfunction, which ultimately lead to diabetic vascular complications and can augment atherosclerotic plaque development and progression at predilection sites.14
Tekabe et al11 demonstrate, for the first time, the noninvasive specific detection of RAGE in the vessel wall. A nondiabetic atherosclerotic apolipoprotein E–deficient mouse model was used for this purpose, and a nuclear imaging technique was applied. A classical molecular imaging approach was chosen, with the creation of polyclonal antibodies against RAGE that were subsequently digested to F(ab)2 fragments and conjugated to a 99mTc radionuclide reporter. Validation was provided with fluorescent conjugated F(ab)2 fragments and showed that the RAGE-conjugated probe localized mainly to macrophages but also endothelial cells and smooth muscle cells. This corresponds to the cell types staining positive for RAGE on histological sections and shows that the RAGE-specific probe was effective in reaching its target in the vessel wall.
Clearly, there are limitations to this study. First, a nontomographic imaging system with a low spatial resolution was used, therefore limiting detailed delineation of RAGE detection in the arterial wall. A tomographic micro-SPECT/CT system would have allowed a significantly better resolution. Another limitation is that polyclonal antibodies were used, which compared with monoclonal antibodies, have less specificity and higher background signal. Nevertheless, the study convincingly demonstrates the noninvasive detection of RAGE in the vessel wall of euglycemic atherosclerotic mice. Another important fact to consider is that RAGE promotes the expression of both matrix metalloproteinases and tissue factor, which both contribute to atherosclerotic plaque rupture and thrombosis. Therefore, the noninvasive detection of RAGE in the vessel wall could help define its role in plaque rupture, which has potentially important clinical implications. The study by Tekabe et al11 therefore represents significant progress in characterization of the biological role of RAGE.
In addition to its role in atherosclerosis and the development of vascular complication in diabetes, RAGE possesses wider implications in a variety of diseases, such as arthritis, cancer, liver disease, neurodegenerative disease, and sepsis, which underscores the importance of the ability of its noninvasive detection.13 Another exciting aspect is that, currently, specific RAGE inhibitors are being developed by the same group. Now having the ability to detect RAGE noninvasively, one can envision the noninvasive monitoring of treatment responses after application of RAGE inhibitors, at least in animal models, which will lead to the streamlined selection of potential drug candidates. In this context, high-affinity inhibitors can be functionalized with radionuclides and applied for imaging purposes as well as for validation of effective drug targeting.15
The hope can now be that the biological role of RAGE can be studied noninvasively in vivo, which will clarify its role in many disease conditions and lead to better treatment of diabetic complications, atherosclerosis, and other diseases in which RAGE is implicated.
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Acknowledgments |
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Disclosures
None.
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Footnotes |
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The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
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