Eliciting α7‐nAChR exerts cardioprotective effects on ischemic cardiomyopathy via activation of AMPK signalling

Abstract

Our previous studies have reported that agonist of α7 nicotinic acetylcholine receptors prevented electrophysiological dysfunction of rats with ischaemic cardiomyopathy (ICM) by eliciting the cholinergic anti‐inflammatory pathway (CAP). Adenosine monophosphate‐activated protein kinase (AMPK) signalling is widely recognized exerting cardioprotective effect in various cardiomyopathy. Here, we aimed to investigate whether the protective effects of the CAP are associated with AMPK signalling in ICM. In vivo, coronary artery of rats was ligated for 4 weeks to induce the ICM and then treated with PNU‐282987 (CAP agonist) and BML‐275 dihydrochloride (AMPK antagonist) for 4 weeks. In vitro, primary macrophages harvested from rats were induced inflammation by Lipopolysaccharide (LPS) treatment and then treated with PNU‐282987 and BML‐275 dihydrochloride. In vivo, exciting CAP by PUN‐282987 elicited an activation of AMPK signalling, alleviated ventricular remodeling, modified the cardiac electrophysiological function, reduced the cardiac expression of collagens and inflammatory cytokines and maintained the integrity of ultrastructure in the ischemic heart. However, the benefits of CAP excitation were blunted by AMPK signaling antagonization. In vitro, excitation of the CAP was observed inhibiting the nuclear transfer of NF‐κB p65 of macrophages and promoting the transformation of Ly‐6C high macrophages into Ly‐6C low macrophages. However, inhibiting AMPK signalling by BML‐275 dihydrochloride reversed the CAP effect on LPS‐treated macrophages. Finally, our findings suggest that eliciting the CAP modulates the inflammatory response in ICM through regulating AMPK signalling.

Targeting α7 nicotinic acetylcholine receptors for chronic pain

“…Their further study confirmed that repeated intrathecal injection of PHA-543613 during the perioperative period shortened the duration of post-surgical pain after SPS and suppressed SPS-potentiated microglia activation, which was also abolished by pretreatment with MLA (Sun et al, 2019). Consistently, Ji et al (2019) validated that intrathecal injection of PHA-543613 significantly alleviated spinal nerve ligation-induced neuropathic pain by decreasing dynorphin A concentration in the ipsilateral spinal cord. Furthermore, Umana et al (2017) revealed that both systemic and intra-vlPAG administration of PHA-543613 significantly attenuated formalin-induced inflammatory pain, which was completely abolished by pretreatment with MLA.…”

Cholinergic Elicitation Prevents Ventricular Remodeling via Alleviations of Myocardial Mitochondrial Injury Linked to Inflammation in Ischemia-Induced Chronic Heart Failure Rats

“…Thus, immunohistochemistry was performed to examine cardiac macrophage infiltration. In a prior study, stimulating the CAP was shown to promote the transformation of Ly-6C high macrophages to Ly-6C low macrophages in the late infarction phase [ 17 ]. Similarly, our results showed that cholinergic evocation reduced the accumulation of M1 macrophages and increased M2 macrophages infiltration in the peri-infarct area.…”

“…B7007, USA) was dissolved in 0.2% DMSO organic solvent and thoroughly oscillated at 37°C until the particles had completely dissociated. Cholinergic stimulation was conducted for 4 weeks with PNU-282987 (1 mg/kg) via a slow intraperitoneal injection for 2 minutes in the CHF rats [ 17 ].…”

“…Emerging evidence showed that cholinergic stimulation was able to improve cardiac remodeling and hemodynamics in the postinfarction rats, and this effect was reversed by the peripheral blockade of α 7nAChR [ 16 ]. Other studies demonstrated the beneficial effect of activating the CAP on the arrhythmogenic substrate with ischemic cardiomyopathy, and the underlying mechanisms rely on the inflammation resolution and cardiac fibrosis attenuation [ 17 , 18 ]. There are no ongoing studies regarding whether CAP elicitation ameliorates the myocardial mitochondrial injuries in the postinfarction state.…”

COVID-19-related myocarditis and cholinergic anti-inflammatory pathways

“…It is encoded by AHRNA7 on chromosome 15q14 and is widely expressed on the surfaces of inflammatory cells including macrophages, monocytes, T cells, B cells, and dendritic cells. [72] , [73] , [74] , [75] …”