PMID- 33791350
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20210402
IS  - 2297-055X (Print)
IS  - 2297-055X (Electronic)
IS  - 2297-055X (Linking)
VI  - 8
DP  - 2021
TI  - Donepezil Ameliorates Pulmonary Arterial Hypertension by Inhibiting M2-Macrophage 
      Activation.
PG  - 639541
LID - 10.3389/fcvm.2021.639541 [doi]
LID - 639541
AB  - 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.
CI  - Copyright (c) 2021 Qiu, Zhang, Li, Jiang, Guo, He and Guo.
FAU - Qiu, Haihua
AU  - Qiu H
AD  - Department of Cardiovascular Medicine, The Affiliated Zhuzhou Hospital Xiangya 
      Medical College, Central South University, Zhuzhou, China.
FAU - Zhang, Yibo
AU  - Zhang Y
AD  - Department of Ultrasound, The Affiliated Zhuzhou Hospital Xiangya Medical 
      College, Central South University, Zhuzhou, China.
FAU - Li, Zhongyu
AU  - Li Z
AD  - Laboratory Medicine Center, The Affiliated Zhuzhou Hospital Xiangya Medical 
      College, Central South University, Zhuzhou, China.
FAU - Jiang, Ping
AU  - Jiang P
AD  - Department of Cardiovascular Medicine, The Affiliated Zhuzhou Hospital Xiangya 
      Medical College, Central South University, Zhuzhou, China.
FAU - Guo, Shuhong
AU  - Guo S
AD  - Department of Cardiovascular Medicine, The Affiliated Zhuzhou Hospital Xiangya 
      Medical College, Central South University, Zhuzhou, China.
FAU - He, Yi
AU  - He Y
AD  - Department of Cardiovascular Medicine, The Affiliated Zhuzhou Hospital Xiangya 
      Medical College, Central South University, Zhuzhou, China.
FAU - Guo, Yuan
AU  - Guo Y
AD  - Department of Cardiovascular Medicine, The Affiliated Zhuzhou Hospital Xiangya 
      Medical College, Central South University, Zhuzhou, China.
AD  - Department of Cardiovascular Medicine, Xiangya Hospital, Central South 
      University, Changsha, China.
LA  - eng
PT  - Journal Article
DEP - 20210315
PL  - Switzerland
TA  - Front Cardiovasc Med
JT  - Frontiers in cardiovascular medicine
JID - 101653388
PMC - PMC8005547
OTO - NOTNLM
OT  - M2-macrophage
OT  - cholinesterase inhibitor
OT  - donepezil
OT  - pulmonary arterial hypertension
OT  - pulmonary arterial smooth muscle cells
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2021/04/02 06:00
MHDA- 2021/04/02 06:01
PMCR- 2021/01/01
CRDT- 2021/04/01 06:31
PHST- 2020/12/09 00:00 [received]
PHST- 2021/02/17 00:00 [accepted]
PHST- 2021/04/01 06:31 [entrez]
PHST- 2021/04/02 06:00 [pubmed]
PHST- 2021/04/02 06:01 [medline]
PHST- 2021/01/01 00:00 [pmc-release]
AID - 10.3389/fcvm.2021.639541 [doi]
PST - epublish
SO  - Front Cardiovasc Med. 2021 Mar 15;8:639541. doi: 10.3389/fcvm.2021.639541. 
      eCollection 2021.