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.
Highlights
Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by progressive pulmonary vascular remodeling and increased right ventricular (RV) afterload, which eventually leads to right heart failure [1]
Histological analyses of pulmonary arterioles showed an increased pulmonary arterial wall thickness (WT, %) from 22.3% in the control group to 63.0% in the MCT group, which decreased to 41.0% after DON treatment (P < 0.05, Figures 1A,B)
DON significantly reduced AchE activity in the plasma and lung tissue of MCT rats by 2.1and 2.5-fold, respectively. This result indicates that DON effectively enhance the parasympathetic activity by inhibiting AchE activity in PAH
Summary
Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by progressive pulmonary vascular remodeling and increased right ventricular (RV) afterload, which eventually leads to right heart failure [1]. Exploring the factors and mechanisms leading to the abnormal proliferation and apoptosis of PASMCs may be beneficial for PAH therapy. Pugliese et al [8] observed the accumulation of cluster of differentiation 68+ (CD68+) and F4/80+ macrophages in the perivascular lung tissue in a mouse model of early-stage hypoxiainduced PAH through qualitative histologic and flow cytometry approaches, respectively. This indicated that robust recruitment and activation of macrophages as well as the production of an array of inflammatory factors play an important role in aggravating pulmonary artery remodeling and PAH [8, 9]. An oral cholinesterase inhibitor, enhances parasympathetic activity by inhibiting acetylcholinesterase, whose therapeutic effects in PAH and its mechanism deserve to be investigated
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