Donepezil Ameliorates Pulmonary Arterial Hypertension by Inhibiting M2-Macrophage Activation

Abstract

Background: The beneficial effects of parasympathetic stimulation in pulmonary arterial hypertension (PAH) have been reported. However, the specific mechanism has not been completely clarified. Donepezil, an oral cholinesterase inhibitor, enhances parasympathetic activity by inhibiting acetylcholinesterase, whose therapeutic effects in PAH and its mechanism deserve to be investigated.Methods: The PAH model was established by a single intraperitoneal injection of monocrotaline (MCT, 50 mg/kg) in adult male Sprague-Dawley rats. Donepezil was administered via intraperitoneal injection daily after 1 week of MCT administration. At the end of the study, PAH status was confirmed by echocardiography and hemodynamic measurement. Testing for acetylcholinesterase activity and cholinergic receptor expression was used to evaluate parasympathetic activity. Indicators of pulmonary arterial remodeling and right ventricular (RV) dysfunction were assayed. The proliferative and apoptotic ability of pulmonary arterial smooth muscle cells (PASMCs), inflammatory reaction, macrophage infiltration in the lung, and activation of bone marrow-derived macrophages (BMDMs) were also tested. PASMCs from the MCT-treated rats were co-cultured with the supernatant of BMDMs treated with donepezil, and then, the proliferation and apoptosis of PASMCs were evaluated.Results: Donepezil treatment effectively enhanced parasympathetic activity. Furthermore, it markedly reduced mean pulmonary arterial pressure and RV systolic pressure in the MCT-treated rats, as well as reversed pulmonary arterial remodeling and RV dysfunction. Donepezil also reduced the proliferation and promoted the apoptosis of PASMCs in the MCT-treated rats. In addition, it suppressed the inflammatory response and macrophage activation in both lung tissue and BMDMs in the model rats. More importantly, donepezil reduced the proliferation and promoted the apoptosis of PASMCs by suppressing M2-macrophage activation.Conclusion: Donepezil could prevent pulmonary vascular and RV remodeling, thereby reversing PAH progression. Moreover, enhancement of the parasympathetic activity could reduce the proliferation and promote the apoptosis of PASMCs in PAH by suppressing M2-macrophage activation.

Inhibition of Th17 cells by donepezil ameliorates experimental lung fibrosis and pulmonary hypertension

“…Evidence demonstrates that parasympathetic activation exerts key cardiovascular protection via the “cholinergic anti-inflammatory pathway,” which mainly refers to innate immunity 10 , 11 . Both our and other studies reported that parasympathetic activation markedly reduced pulmonary arterial pressure and improved right heart function in Group I PH animal models, which is primarily dependent on its potent anti-inflammatory function via inhibiting macrophage 12 - 14 . Thus, the anti-inflammatory role of parasympathetic activation has been regarded as the intermediate hub of neuroimmune regulation 10 .…”

“…Recently, Vang et al 34 found that α7nAChR activation led to an increase in adult ventricular fibroblast proliferation and collagen content, and inhibition of α7nAChR is a potentially novel therapeutic strategy in the setting of increased RV afterload in a PH model. Previously, we observed that parasympathetic activity protected against PH by downregulating α7nAchR expression 14 . Similarly, in this study, the AchE and α7nAchR levels were also assayed to verify the underlying mechanism of DON in BLM-induced mice, and α7nAchR was considered a key factor in the regulation of Th17 cell differentiation.…”

“…Similarly, Yoshida et al 13 used vagus nerve stimulation (VNS) to restore autonomic balance, in which they observed that parasympathetic activity effectively ameliorated pulmonary vascular remodeling and preserved RV function in an animal model 13 . In a previous study, we showed that DON-enhanced parasympathetic activity could effectively reverse the course of pulmonary arterial hypertension in monocrotaline‑induced rats by inhibiting macrophage activation 14 . Interestingly, these beneficial effects of parasympathetic activity for PH are associated with Group I PH.…”

Role of macrophages in pulmonary arterial hypertension

“…Studies have shown that whole lung samples show up-regulation of pro-inflammatory M1 and alternatively activated M2 macrophage markers in a hypoxia-induced PAH model ( 52 ). A recent study showed that the inhibition of M2-type macrophage activation by Donepezil in monocrotaline (MCT)-treated rats could effectively reduce the proliferation of PASMCs and improve pulmonary vascular remodeling ( 53 ). To further verify the presence of altered macrophage polarization in PAH patients, it was investigated that an M1/M2 imbalance was observed between macrophage low (MacLow) bone marrow-derived macrophages in men and monocyte-derived macrophages in PAH patients under doxycycline and interleukin-4 (IL-4) stimulation.…”

Research progress on detection techniques for point-of-care testing of foodborne pathogens

“…Foodborne pathogens continue to cause many intestinal diseases in humans around the world, causing a huge health and economic burden ( Ling et al, 2019 ; Akter et al, 2021 ; Prata et al, 2021 ; Qiu et al, 2021 ). Figures from the World Health Organization (WHO) estimate that about 2 billion people die each year from diarrhea or disease caused by contaminated food, and 30% of them are children under 5 years of age ( Scallan Walter et al, 2020 ; Belina et al, 2021 ; Van Puyvelde et al, 2021 ).…”