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Published on: March 30, 2018
Activating α7nAChR helps post-myocardial infarction healing by regulating macrophage polarization via the STAT3
Xiao-Hui Niu1,2, Rong-Hua Liu1,2, Xiao Lv1,2
1Department of Cardiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China.
Insights
Activating the alpha7 nicotinic acetylcholine receptor (α7nAChR) with PNU282987 improves cardiac function after myocardial infarction (MI) by reducing pro-inflammatory monocytes and enhancing beneficial macrophages. This suggests α7nAChR as a therapeutic target for MI recovery.
Area of Science:
- Cardiovascular Research
- Immunology
- Pharmacology
Background:
- Monocytes and macrophages are key players in inflammation and cardiac remodeling post-myocardial infarction (MI).
- The cholinergic anti-inflammatory pathway (CAP), via α7 nicotinic acetylcholine receptors (α7nAChR), regulates inflammatory responses in monocytes/macrophages.
Purpose of the Study:
- To investigate the role of α7nAChR in modulating monocyte/macrophage recruitment and polarization following MI.
- To assess the impact of α7nAChR activation on cardiac remodeling and function after MI.
Main Methods:
- Rats underwent coronary ligation and received α7nAChR agonist (PNU282987) or antagonist (MLA).
- In vitro studies used RAW264.7 cells stimulated with LPS+IFN-γ and treated with PNU282987, MLA, or STAT3 inhibitor (S3I-201).
- Cardiac function, fibrosis, capillary density, and macrophage polarization (M1/M2) were assessed using echocardiography, histology, immunofluorescence, and flow cytometry.
Main Results:
- PNU282987 treatment improved cardiac function, reduced fibrosis, and decreased 28-day mortality post-MI.
- PNU282987 modulated monocyte subsets and promoted M2 macrophage polarization while inhibiting M1 polarization in vitro, effects reversed by S3I-201.
- MLA administration produced opposite effects, worsening cardiac outcomes.
Conclusions:
- Activation of α7nAChR inhibits pro-inflammatory monocyte/macrophage recruitment during the early phase of MI.
- Targeting α7nAChR improves cardiac function and remodeling following MI.
- α7nAChR represents a promising therapeutic target for managing monocyte/macrophage phenotypes and promoting cardiac healing post-MI.
Background:
Monocytes/macrophages play critical roles in inflammation and cardiac remodeling following myocardial infarction (MI). The cholinergic anti-inflammatory pathway (CAP) modulates local and systemic inflammatory responses by activating α7 nicotinic acetylcholine receptors (α7nAChR) in monocytes/macrophages. We investigated the effect of α7nAChR on MI-induced monocyte/macrophage recruitment and polarization and its contribution to cardiac remodeling and dysfunction.
Methods:
Adult male Sprague Dawley rats underwent coronary ligation and were intraperitoneally injected with the α7nAChR-selective agonist PNU282987 or the antagonist methyllycaconitine (MLA). RAW264.7 cells were stimulated with lipopolysaccharide (LPS) + interferon-gamma (IFN-γ) and treated with PNU282987, MLA, and S3I-201 (a STAT3 inhibitor). Cardiac function was evaluated by echocardiography. Masson's trichrome and immunofluorescence were used to detect cardiac fibrosis, myocardial capillary density, and M1/M2 macrophages. Western blotting was used to detect protein expression, and the proportion of monocytes was measured using flow cytometry.
Results:
Activating the CAP with PNU282987 significantly improved cardiac function and reduced cardiac fibrosis and 28-day mortality after MI. On days 3 and 7 post-MI, PNU282987 reduced the percentage of peripheral CD172a + CD43low monocytes and the infiltration of M1 macrophages in the infarcted hearts, whereas it increased the recruitment of peripheral CD172a + CD43high monocytes and M2 macrophages. Conversely, MLA exerted the opposite effects. In vitro, PNU282987 inhibited M1 macrophage polarization and promoted M2 macrophage polarization in LPS + IFN-γ-stimulated RAW264.7 cells. These PNU282987-induced changes in LPS + IFN-γ-stimulated RAW264.7 cells were reversed by administering S3I-201.
Conclusion:
Activating α7nAChR inhibits the early recruitment of pro-inflammatory monocytes/macrophages during MI and improves cardiac function and remodeling. Our findings suggest a promising therapeutic target for regulating monocyte/macrophage phenotypes and promoting healing after MI.
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