Atherosclerosis Plaque Heterogeneity and Response to Therapy Detected by In Vivo Molecular Imaging of Matrix Metalloproteinase Activation

Abstract

Matrix metalloproteinases (MMPs) play a key role in the development of atherosclerosis and its complications. In vivo detection and quantification of MMP activation can help track the propensity to complications and response to therapy. We sought to establish an in vivo imaging approach for monitoring MMP activation in atherosclerotic mouse aorta and use it to assess the response to dietary modification. Method and Results Apo E−/− mice were fed normal chow or a high fat diet (HFD) for up to 3 months or HFD for 2 months followed by 1 month on normal chow. After three months of HFD, there was considerable atherosclerosis in the aorta. In vivo microSPECT/CT imaging using RP782 (an 111In-labeled tracer targeting activated MMPs) showed a heterogeneous pattern of tracer uptake along the aorta. Heterogeneity of RP782 uptake was confirmed by autoradiography, and specificity was demonstrated using excess unlabeled precursor. Tracer uptake quantified by microSPECT imaging significantly correlated with uptake quantified by autoradiography. Comparison of Oil Red O staining with autoradiography demonstrated areas of discordance between plaque presence and tracer uptake. HFD withdrawal led to significant reduction in RP782 uptake beyond the effect on plaque area. MMP expression and macrophage infiltration were similarly heterogeneous along the aorta and significantly reduced following withdrawal from the HFD. Finally, RP782 uptake significantly correlated with aortic macrophage content. Conclusion Molecular imaging of MMP activation reveals the heterogeneity of atherosclerotic plaques and is a useful tool for tracking plaque biology and response to therapy.

Preclinical Evaluation of RYM1, a Matrix Metalloproteinase–Targeted Tracer for Imaging Aneurysm

“…Accordingly, in vivo imaging of MMP activation may help predict the evolution of the disease and guide therapeutic decisions. The feasibility and potential value of in vivo MMP-targeted imaging in cardiovascular pathology has been shown in preclinical studies (11)(12)(13)(14)(15)(16)(17)(18). Many of these studies have used a macrocyclic pan-MMP targeting tracer, 99m Tc-RP805, which, based on existing preclinical data, is well-positioned to serve as a lead agent for further development.…”

Matrix metalloproteinases in atherosclerosis: role of nitric oxide, hydrogen sulfide, homocysteine, and polymorphisms

“…Several of these cells are activated, and produce inflammatory cytokines like IFNγ and TNF 6. The anatomy of the plaque is made up of a thin fibrous cap, necrotic core, outward remodeling, and many inflammatory cells 7. The different mediators of atherosclerosis can be visualized in Figure 2.…”

Molecular Imaging of the Cardiac Extracellular Matrix

“…[92][93][94][95] Specificity of the tracer and correlation with MMP2 and MMP9 activity and presence of macrophages was shown. 92 Also, imaging with Tc-RP805, has been undertaken in animal models of MI, 90 atherosclerosis, 96 carotid damage, 97 and carotid aneurysms. 98 The feasibility of MRI of MMP using gadolinium-labeled probe (P947) has been demonstrated in rat model of aortic aneurysm, 99 mouse 100,101 and rabbit 100,101 models of atherosclerosis, and excised human carotid atherosclerotic plaques.…”