Multimodality and Molecular Imaging of Matrix Metalloproteinase Activation in Calcific Aortic Valve Disease

Jung, Jaejoon; Razavian, Mahmoud; Challa, Azariyas A.; Nie, Lei; Golestani, Reza; Zhang, Jiasheng; Ye, Yunpeng; Russell, Kerry S.; Robinson, Simon P.; Heistad, Donald D.; Sadeghi, Mehran M.

doi:10.2967/jnumed.114.152355

Cited by 38 publications

(36 citation statements)

References 29 publications

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“…MicroSPECT/CT imaging was performed as described previously with some modification 19 . RP805 (37 MBq) or its 99m Tc-labeled amide analog, as a negative control tracer, were administered through a jugular vein catheter.…”

Section: Methodsmentioning

confidence: 99%

“…After microSPECT and CT image acquisition the animals were euthanized and lungs, heart and aorta were harvested for planar imaging and histology (the right lung was used for ex vivo imaging and the left lung was snap-frozen in OCT for further RNA and protein analysis). MicroSPECT data were reconstructed and analyzed as described 19 . For image analysis, spherical regions of interest were drawn in the lungs based on microCT images.…”

Section: Methodsmentioning

confidence: 99%

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Matrix Metalloproteinase–Targeted Imaging of Lung Inflammation and Remodeling

Golestani

Razavian

et al. 2016

J Nucl Med

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Imaging techniques for detection of molecular and cellular processes that precede or accompany lung diseases are needed. Matrix metalloproteinases (MMPs) play key roles in the development of pulmonary pathology. Objectives Investigate the feasibility of in vivo MMP-targeted molecular imaging for detection of lung inflammation and remodeling. Methods Lung-specific IL-13 transgenic [Club cell 10-kDa protein (CC10)-IL-13Tg)] mice, and wild type (WT) littermates were used in this study. Lung structure, gene expression, and MMP activity were assessed by histology, real-time reverse transcription polymerase chain reaction, Western blot and zymography. MMP activation was imaged by in vivo micro single-photon emission computed tomography (SPECT)/CT followed by ex vivo planar imaging. Signal specificity was addressed using a control tracer. The correlation between in vivo MMP signal and gene expression was addressed. Results CC10-IL-13Tg mice developed considerable pulmonary tissue remodeling and inflammation. CD68, MMP-12 and MMP-13 were significantly higher in CC10-IL-13Tg lungs. On in vivo microSPECT/CT and ex vivo planar images, the MMP signal was significantly higher in the lungs of CC10-IL-13Tg mice than WT animals. Furthermore, a non-binding analog tracer showed significantly lower accumulation in CC10-IL-13Tg lungs relative to the specific tracer. There was a significant correlation between microSPECT/CT-derived MMP signal and CD68 expression in the lungs (r = 0.70, P < 0.01). Conclusions MicroSPECT/CT-based MMP-targeted imaging of the lungs is feasible and reflects pulmonary inflammation. If validated in humans, molecular imaging of inflammation and remodeling can potentially help early diagnosis and monitoring of the effects of therapeutic interventions in pulmonary diseases.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Matrix Metalloproteinase–Targeted Imaging of Lung Inflammation and Remodeling

Golestani

Razavian

et al. 2016

J Nucl Med

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the limited hydrosolubility of RP805 precursor is a barrier to establishing uptake specificity in vivo. As such, only a few studies, mainly in vascular and valvular disease models, have attempted to demonstrate uptake specificity of this imaging agent in vivo (15,17). We sought to address these limitations by modifying the structure of the precursor, which would improve hydrophilicity and possibly blood clearance, without affecting MMP binding.…”

Section: Discussionmentioning

confidence: 99%

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

Toczek

Gona

et al. 2017

J Nucl Med

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Matrix metalloproteinases (MMPs) play a key role in abdominal aortic aneurysm (AAA) development. Accordingly, MMP-targeted imaging provides important information regarding vessel wall biology in the course of aneurysm development. Given the small size of the vessel wall and its proximity with blood, molecular imaging of aneurysm optimally requires highly sensitive tracers with rapid blood clearance. To this end, we developed a novel hydrosoluble zwitterionic MMP inhibitor, RYM, on the basis of which a pan-MMP tracer, RYM1, was designed. Here, we describe the development and preclinical evaluation of RYM1 in comparison with RP805, a commonly used pan-MMP tracer in murine models of aneurysm. Methods: The macrocyclic hydroxamate-based pan-MMP inhibitor coupled with 6-hydrazinonicotinamide, RYM1, was synthesized and labeled with 99m Tc. Radiochemical stability of 99m Tc-RYM1 was evaluated by radio-high-performance liquid chromatography analysis. Tracer blood kinetics and biodistribution were compared with 99m Tc-RP805 in C57BL/6J mice (n 5 10). 99m Tc-RYM1 binding to aneurysm and specificity were evaluated by quantitative autoradiography in apolipoprotein E-deficient (apoE 2/2 ) mice with CaCl 2 -induced carotid aneurysm (n 5 11). Angiotensin II-infused apoE 2/2 (n 5 16) mice were used for small-animal SPECT/CT imaging. Aortic tissue MMP activity and macrophage marker CD68 expression were assessed by zymography and reverse-transcription polymerase chain reaction. Results: RYM1 showed nanomolar range inhibition constants for several MMPs. 99m Tc-RYM1 was radiochemically stable in mouse blood for 5 h and demonstrated rapid renal clearance and lower blood levels in vivo compared with 99m Tc-RP805. 99m Tc-RYM1 binding to aneurysm and its specificity were shown by autoradiography in carotid aneurysm. Angiotensin II infusion in apoE 2/2 mice for 4 wk resulted in AAA formation in 36% (4/11) of surviving animals. In vivo 99m Tc-RYM1 small-animal SPECT/ CT images showed higher uptake of the tracer in AAA than nondilated aortae. Finally, aortic uptake of 99m Tc-RYM1 in vivo correlated with aortic MMP activity and CD68 expression. Conclusion: The newly developed pan-MMP inhibitor-based tracer 99m Tc-RYM1 displays favorable pharmacokinetics for early vascular imaging and enables specific detection of inflammation and MMP activity in aneurysm. Abdomi nal aortic aneurysm (AAA) accounts for 10,000-15,000 recorded deaths, mainly due to rupture, in the United States each year. Current clinical guidelines for surgical repair of AAA are based on aneurysm size, expansion rate, and clinical symptoms (1). However, a significant portion of AAA ruptures occurs in patients who do not meet the criteria for AAA repair, and some large AAAs may remain stable for many years. As such, new risk-stratification tools are needed to overcome the limitations of the current approach to patient selection for AAA repair. Molecular imaging targeted at the determinants of AAA expansion and rupture appears particularly promising in this regard (2). Matrix me...

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“…In the current study, an MMP targeting probe was evaluated. Besides a role in remodeling, MMP play an important role in various other cardiovascular diseases, including atherosclerosis, [23][24][25][26][27][28][29] calcific aortic valve disease, 30 aortic aneurysm formation, 31 and pulmonary inflammation. 32 Moreover, MMP also play a role in non-cardiac diseases, notably malignancy.…”

Section: See Related Article Pp 1114-1123mentioning

confidence: 99%

Playing slot to hitting the jackpot in molecular imaging: On probability of uncovering subcellular pathogenesis vs achieving clinical applicability

Haas

Narula

2018

Journal of Nuclear Cardiology

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Myocardial infarction (MI), despite optimal reperfusion therapy, results in substantial loss of muscle tissue through apoptosis and necrosis. The repair process post MI is traditionally divided into consecutive and partly overlapping inflammation, proliferation, and maturation phases. The initial phase is characterized by infiltration of inflammatory cells removing cellular debris, and formation of new blood vessels. Matrix metalloproteinases (MMP) and other proteolytic enzymes secreted by inflammatory cells facilitate these processes. During the proliferatory phase, fibroblasts transdifferentiate into myofibroblasts and deposit collagen in the infarct area. This is mediated by a variety of growth factors, including components of a local reninangiotensin-aldosterone system. In the final phase, the newly formed scar is consolidated through cross-linking of collagen fibers and other extracellular matrix components. The extracellular matrix plays an important role in the healing process, and an imbalance between matrix deposition and degradation can lead to adverse myocardial remodeling spiraling to heart failure. Excessive collagen deposition beyond the infarct area contributes to myocardial stiffening and loss of contractile function. On the other hand, inadequate deposition of collagen or excessive collagen degradation can lead to infarct expansion, aneurysm formation, left ventricular (LV) dilation, and even cardiac rupture.MMP are a group of zinc-dependent enzymes that degrade a large variety of extracellular matrix proteins. Approximately 25 MMP have been described and classified in the functional subgroups gelatinases, collagenases, stromelysins, and membrane-type MMP. Extensive preclinical work has suggested detrimental effect of the gelatinases MMP-2 and MMP-9. Genetic knockout of MMP-9 1,2 and MMP-2 3 restricted inflammatory response and removal of necrotic tissue and collagen deposition after experimental MI; this was associated with reduction in LV dilation and incidence of of LV rupture. Moreover, knockout of endogenous tissue inhibitors of metalloproteinases (TIMP) resulted in increased hypertrophy, dilation, and cardiac dysfunction.4,5 Also, animal studies have shown that pharmacologic MMP inhibitors reduce remodeling.6,7 Therapeutic MMP inhibition has not been successfully translated to clinical efficacy.Targeting of cardiac MMP activity has been reported using optical imaging 8 and nuclear imaging [9][10][11] probes. A non-invasive SPECT imaging of MMP activity has been reported in experimental MI in mice employing Tc-99 m-labeled broad-spectrum MMP inhibitor RP805. 10 When comparing with control mice, uptake in infarct area was fivefold higher from week 1 to 3, with slight reduction over time. Interestingly, uptake was also twofold higher in remote area, suggesting that remote imaging could become feasible. In a follow-up study by the same group, the same probe was evaluated in a larger infarct model in porcine experiments.

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Multimodality and Molecular Imaging of Matrix Metalloproteinase Activation in Calcific Aortic Valve Disease

Cited by 38 publications

References 29 publications

Matrix Metalloproteinase–Targeted Imaging of Lung Inflammation and Remodeling

Matrix Metalloproteinase–Targeted Imaging of Lung Inflammation and Remodeling

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

Playing slot to hitting the jackpot in molecular imaging: On probability of uncovering subcellular pathogenesis vs achieving clinical applicability

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