GSAO-based molecular targeting of myocardial necrosis in acute ischemic insult
| Autor: | Hans Haas, H. J., Zandbergen, H. R., Tahara, N., Petrov, A. D., Riemer Slart, Hendrikus Boersma, Reutelingsperger, C. P., Narula, J. |
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| Přispěvatelé: | Vascular Ageing Programme (VAP), Cardiovascular Centre (CVC), Translational Immunology Groningen (TRIGR) |
| Předmět: |
autophagy
ex vivo study heart infarction single photon emission computer tomography rabbit nick end labeling occlusion protein binding perfusion necrosis annexin cell stress caspase 3 cell protein membrane mouse indium 111 marker animal model beclin 1 arsenic apoptosis imaging unfolded protein response acute heart infarction cell death membrane damage immunohistochemistry microscopy heart muscle necrosis |
| Zdroj: | University of Groningen Journal of Nuclear Cardiology, 20(1). SPRINGER |
| ISSN: | 1071-3581 |
| Popis: | Purpose: GSAO has an arsenic group that binds to dithiols on various intracellular proteins that are upregulated during cellular stress including HSP90, PDI, which plays a role in the unfolded protein response and apoptosis, and Beclin-1, which drives autophagy. Extracellular dithiols are uncommon. As 111In-GSAO is membrane impermeable, intracellular uptake shows membrane disruption, a hallmark of necrotic cell death. It is proposed that information about preferential protein binding other than HSP90 would determine the likely initial cell death pathway. The current study sought to show feasibility of GSAO imaging in animal models of acute and chronic myocardial infarction and to evaluate the relation between myocardial apoptosis and necrosis. Methods: Chronic and acute myocardial infarction were induced by persistent occlusion and by 30 minutes occlusion + release of the LAD in rabbits and mice. In acute MI rabbits, in vivo and ex vivo SPECT imaging using GSAO (n = 6), GSAO + sestamibi (n = 4), GSAO + AA5 (n = 3) and control compound GSCA (n = 5) were performed, followed by gamma-counting and immunohistochemistry. In mice, ex vivo imaging and gamma-counting using GSAO was performed after acute MI (n = 6), after chronic MI at 2 (n = 6), 4 (n = 6) and 12 (n = 8) weeks and in controls (n = 5). GSCA was employed at 2 (n = 6) weeks. Six mice received fluorescently labeled AA5 and GSAO after acute MI. Results: In rabbits, myocardial GSAO uptake was high (1.1 ± 0.43%ID/g), localized in the perfusion defect and was significantly higher than in the remote area (0.07 ± 0.03%ID/g, P |
| Databáze: | OpenAIRE |
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