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Activation of Nicotinic Acetylcholine α7 Receptor Attenuates Progression of Monocrotaline-Induced Pulmonary Hypertension in Rats by Downregulating the NLRP3 Inflammasome.
Front Pharmacol. 2019; 10:128.FP

Abstract

Background:

Inflammation and altered immunity contribute to the development of pulmonary arterial hypertension (PH). The alpha 7 nicotinic acetylcholine receptor (α7nAChR) possesses anti-inflammatory activities. The current study was performed to investigate the effects of a selective α7nAChR agonist, PNU-282987, on controlling a monocrotaline (MCT)-induced rat model of PH and explored the underlying mechanisms.

Methods:

Sprague-Dawley rats were injected with MCT and treated with PNU-282987 at the prevention (starting 1 week before MCT) and treatment (starting 2 weeks after MCT) settings. Four weeks after MCT injection, hemodynamic changes, right ventricular structure, and lung morphological features were assessed. Enzyme-linked immunosorbent assay, Western blot and qRT-PCR were performed to assess levels of inflammatory cytokines and NLRP3 (Nod-like receptor family pyrin domain-containing 3) inflammasome pathway in the rat lung tissues. In addition, the lung macrophage line NR8383 was used to confirm the in vivo data.

Results:

Monocrotaline injection produced PH in rats and downregulated α7nAChR mRNA and protein expression in rat lung tissues compared to sham controls. Pharmacological activation of α7nAChR by PNU-282987 therapy improved the rat survival rate, attenuated the development of PH as assessed by remodeling of pulmonary arterioles, reduced the right ventricular (RV) systolic pressure, and ameliorated the hypertrophy and fibrosis of the RV in rats with MCT-induced PH. The expression of TNF-α, IL-6, IL-1β, and IL-18 were downregulated in rat lung tissues, which implied that PNU-282987 therapy may help regulate inflammation. These protective effects involved the inhibition of the NLRP3 inflammasome. In vitro assays of cultured rat lung macrophages confirmed that the anti-inflammation effect of PNU-282987 therapy may contribute to the disturbance of NLRP3 inflammasome activation.

Conclusion:

Targeting α7nAChR with PNU-282987 could effectively prevent and treat PH with benefits for preventing ongoing inflammation in the lungs of rats with MCT-induced PH by inhibiting NLRP3 inflammasome activation.

Authors+Show Affiliations

Department of Ultrasound, The Cardiovascular Disease Institute, The First Affiliated Hospital to Guangxi Medical University, Nanning, China.Department of Ultrasound, The Cardiovascular Disease Institute, The First Affiliated Hospital to Guangxi Medical University, Nanning, China.Department of Cardiology, The First Affiliated Hospital to Guangxi Medical University, Nanning, China.Department of Cardiology, The First Affiliated Hospital to Guangxi Medical University, Nanning, China.Department of Pathology, The First Affiliated Hospital to Guangxi Medical University, Nanning, China.The Experimental Center of Guangxi Medical University, Nanning, China.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30863307

Citation

Deng, Yan, et al. "Activation of Nicotinic Acetylcholine Α7 Receptor Attenuates Progression of Monocrotaline-Induced Pulmonary Hypertension in Rats By Downregulating the NLRP3 Inflammasome." Frontiers in Pharmacology, vol. 10, 2019, p. 128.
Deng Y, Guo SL, Wei B, et al. Activation of Nicotinic Acetylcholine α7 Receptor Attenuates Progression of Monocrotaline-Induced Pulmonary Hypertension in Rats by Downregulating the NLRP3 Inflammasome. Front Pharmacol. 2019;10:128.
Deng, Y., Guo, S. L., Wei, B., Gao, X. C., Zhou, Y. C., & Li, J. Q. (2019). Activation of Nicotinic Acetylcholine α7 Receptor Attenuates Progression of Monocrotaline-Induced Pulmonary Hypertension in Rats by Downregulating the NLRP3 Inflammasome. Frontiers in Pharmacology, 10, 128. https://doi.org/10.3389/fphar.2019.00128
Deng Y, et al. Activation of Nicotinic Acetylcholine Α7 Receptor Attenuates Progression of Monocrotaline-Induced Pulmonary Hypertension in Rats By Downregulating the NLRP3 Inflammasome. Front Pharmacol. 2019;10:128. PubMed PMID: 30863307.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Activation of Nicotinic Acetylcholine α7 Receptor Attenuates Progression of Monocrotaline-Induced Pulmonary Hypertension in Rats by Downregulating the NLRP3 Inflammasome. AU - Deng,Yan, AU - Guo,Sheng-Lan, AU - Wei,Bin, AU - Gao,Xing-Cui, AU - Zhou,Ying-Chuan, AU - Li,Jia-Quan, Y1 - 2019/02/26/ PY - 2018/10/17/received PY - 2019/02/05/accepted PY - 2019/3/14/entrez PY - 2019/3/14/pubmed PY - 2019/3/14/medline KW - NLRP3 inflammasome KW - inflammation KW - pulmonary hypertension KW - pulmonary vascular remodeling KW - α7nACh nicotinic acetylcholine receptor SP - 128 EP - 128 JF - Frontiers in pharmacology JO - Front Pharmacol VL - 10 N2 - Background: Inflammation and altered immunity contribute to the development of pulmonary arterial hypertension (PH). The alpha 7 nicotinic acetylcholine receptor (α7nAChR) possesses anti-inflammatory activities. The current study was performed to investigate the effects of a selective α7nAChR agonist, PNU-282987, on controlling a monocrotaline (MCT)-induced rat model of PH and explored the underlying mechanisms. Methods: Sprague-Dawley rats were injected with MCT and treated with PNU-282987 at the prevention (starting 1 week before MCT) and treatment (starting 2 weeks after MCT) settings. Four weeks after MCT injection, hemodynamic changes, right ventricular structure, and lung morphological features were assessed. Enzyme-linked immunosorbent assay, Western blot and qRT-PCR were performed to assess levels of inflammatory cytokines and NLRP3 (Nod-like receptor family pyrin domain-containing 3) inflammasome pathway in the rat lung tissues. In addition, the lung macrophage line NR8383 was used to confirm the in vivo data. Results: Monocrotaline injection produced PH in rats and downregulated α7nAChR mRNA and protein expression in rat lung tissues compared to sham controls. Pharmacological activation of α7nAChR by PNU-282987 therapy improved the rat survival rate, attenuated the development of PH as assessed by remodeling of pulmonary arterioles, reduced the right ventricular (RV) systolic pressure, and ameliorated the hypertrophy and fibrosis of the RV in rats with MCT-induced PH. The expression of TNF-α, IL-6, IL-1β, and IL-18 were downregulated in rat lung tissues, which implied that PNU-282987 therapy may help regulate inflammation. These protective effects involved the inhibition of the NLRP3 inflammasome. In vitro assays of cultured rat lung macrophages confirmed that the anti-inflammation effect of PNU-282987 therapy may contribute to the disturbance of NLRP3 inflammasome activation. Conclusion: Targeting α7nAChR with PNU-282987 could effectively prevent and treat PH with benefits for preventing ongoing inflammation in the lungs of rats with MCT-induced PH by inhibiting NLRP3 inflammasome activation. SN - 1663-9812 UR - https://www.unboundmedicine.com/medline/citation/30863307/Activation_of_Nicotinic_Acetylcholine_α7_Receptor_Attenuates_Progression_of_Monocrotaline_Induced_Pulmonary_Hypertension_in_Rats_by_Downregulating_the_NLRP3_Inflammasome_ L2 - https://doi.org/10.3389/fphar.2019.00128 DB - PRIME DP - Unbound Medicine ER -
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