Affiliation:
1. The University of Edinburgh
2. Kaunas University of Technology: Kauno Technologijos Universitetas
3. The University of Edinburgh The Roslin Institute
4. Copenhagen University Hospital: Rigshospitalet
Abstract
Abstract
Background
Cardiac repair and remodeling following myocardial infarction (MI) is a multifactorial process involving pro-reparative inflammation, angiogenesis and fibrosis. Non-invasive imaging using a radiotracer targeting these processes could provide a key research tool to understand the underlying mechanisms in cardiac wound healing. Activation of the alpha7 nicotinic acetylcholine receptor (ɑ7nAChR) stimulates pro-reparative macrophage activity and angiogenesis. We investigated whether this target could serve as an imaging biomarker for these interlinked wound healing responses by assessing in vitro cellular expression and by using a tritiated-version of the PET radiotracer [18F]NS14490 in tissue autoradiography studies.
Results
ɑ7nAChR expression in 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 [3H]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 in specific binding at days 14 and 21. This peak matched the onset of vessel formation and macrophage infiltration. In a rat MI model, specific binding of [3H]NS14490 was low within the myocardium of the sham cohort and the remote myocardium of the MI cohort. Specific binding within the infarcted myocardium 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 MI tissue revealed strong associations between the ɑ7nAChR signal and extracellular matrix deposition.
Conclusion
ɑ7nAChR is highly expressed in macrophages and showed proliferation and hypoxia driven expression in endothelial cells. While NS14490 imaging displays a pattern that coincides with vessel formation and macrophage infiltration in the sponge model, this is not the case in the MI model where the ɑ7nAChR signal strongly associated with extracellular matrix deposition. Overall, these findings support the involvement of ɑ7nAChR across several processes central to cardiac repair and warrant further investigation to assess the role of ɑ7nAChR in fibrosis and establish the relationship with cardiac function during adverse remodelling.
Publisher
Research Square Platform LLC
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