Assessment of the alpha 7 nicotinic acetylcholine receptor as an imaging marker of cardiac repair-associated processes using NS14490.

Autor: Reid VJM; Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, UK.; Edinburgh Imaging, The University of Edinburgh, Edinburgh, UK., McLoughlin WKX; Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, UK., Pandya K; Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, UK.; Edinburgh Imaging, The University of Edinburgh, Edinburgh, UK., Stott H; Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, UK., Iškauskienė M; Department of Organic Chemistry, Kaunas University of Technology, Kaunas, Lithuania., Šačkus A; Department of Organic Chemistry, Kaunas University of Technology, Kaunas, Lithuania., Marti JA; Proteomics and Metabolomics Facility, The Roslin Institute, University of Edinburgh, Edinburgh, UK., Kurian D; Proteomics and Metabolomics Facility, The Roslin Institute, University of Edinburgh, Edinburgh, UK., Wishart TM; Proteomics and Metabolomics Facility, The Roslin Institute, University of Edinburgh, Edinburgh, UK., Lucatelli C; Edinburgh Imaging, The University of Edinburgh, Edinburgh, UK., Peters D; DanPET AB, Malmo, Sweden.; Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark., Gray GA; Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, UK., Baker AH; Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, UK., Newby DE; Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, UK., Hadoke PWF; Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, UK., Tavares AAS; Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, UK.; Edinburgh Imaging, The University of Edinburgh, Edinburgh, UK., MacAskill MG; Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, UK. mark.macaskill@ed.ac.uk.; Edinburgh Imaging, The University of Edinburgh, Edinburgh, UK. mark.macaskill@ed.ac.uk.
Jazyk: angličtina
Zdroj: EJNMMI research [EJNMMI Res] 2024 Jan 11; Vol. 14 (1), pp. 7. Date of Electronic Publication: 2024 Jan 11.
DOI: 10.1186/s13550-023-01058-2
Abstrakt: Background: Cardiac repair and remodeling following myocardial infarction (MI) is a multifactorial process involving pro-reparative inflammation, angiogenesis and fibrosis. Noninvasive imaging using a radiotracer targeting these processes could be used to elucidate cardiac wound healing mechanisms. The alpha7 nicotinic acetylcholine receptor (ɑ7nAChR) stimulates pro-reparative macrophage activity and angiogenesis, making it a potential imaging biomarker in this context. We investigated this by assessing in vitro cellular expression of ɑ7nAChR, and by using a tritiated version of the PET radiotracer [ 18 F]NS14490 in tissue autoradiography studies.
Results: ɑ7nAChR expression in human monocyte-derived macrophages and vascular cells showed the highest relative expression was within macrophages, but only endothelial cells exhibited a proliferation and hypoxia-driven increase in expression. Using a mouse model of inflammatory angiogenesis following sponge implantation, specific binding of [ 3 H]NS14490 increased from 3.6 ± 0.2 µCi/g at day 3 post-implantation to 4.9 ± 0.2 µCi/g at day 7 (n = 4, P < 0.01), followed by a reduction at days 14 and 21. This peak matched the onset of vessel formation, macrophage infiltration and sponge fibrovascular encapsulation. In a rat MI model, specific binding of [ 3 H]NS14490 was low in sham and remote MI myocardium. Specific binding within the infarct increased from day 14 post-MI (33.8 ± 14.1 µCi/g, P ≤ 0.01 versus sham), peaking at day 28 (48.9 ± 5.1 µCi/g, P ≤ 0.0001 versus sham). Histological and proteomic profiling of ɑ7nAChR positive tissue revealed strong associations between ɑ7nAChR and extracellular matrix deposition, and rat cardiac fibroblasts expressed ɑ7nAChR protein under normoxic and hypoxic conditions.
Conclusion: ɑ7nAChR is highly expressed in human macrophages and showed proliferation and hypoxia-driven expression in human endothelial cells. While NS14490 imaging displays a pattern that coincides with vessel formation, macrophage infiltration and fibrovascular encapsulation in the sponge model, this is not the case in the MI model where the ɑ7nAChR imaging signal was strongly associated with extracellular matrix deposition which could be explained by ɑ7nAChR expression in fibroblasts. Overall, these findings support the involvement of ɑ7nAChR across several processes central to cardiac repair, with fibrosis most closely associated with ɑ7nAChR following MI.
(© 2024. The Author(s).)
Databáze: MEDLINE
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