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Diminazen Aceturate Protects Pulmonary Ischemia-Reperfusion Injury via Inhibition of ADAM17-Mediated Angiotensin-Converting Enzyme 2 Shedding

Lung ischemia-reperfusion (IR) injury is induced by pulmonary artery occlusion and reperfusion. Lung IR injury commonly happens after weaning from extracorporeal circulation, lung transplantation, and pulmonary thromboendarterectomy; it is a lethal perioperative complication. A definite therapeutic...

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Autores principales: Wang, Li-Fang, Sun, Yang-Yang, Pan, Qian, Yin, Yi-Qing, Tian, Xiao-Ming, Liu, Yue, Bu, Tegeleqi, Zhang, Qingy, Wang, Yong-An, Zhao, Jing, Luo, Yuan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8546118/
https://www.ncbi.nlm.nih.gov/pubmed/34712133
http://dx.doi.org/10.3389/fphar.2021.713632
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author Wang, Li-Fang
Sun, Yang-Yang
Pan, Qian
Yin, Yi-Qing
Tian, Xiao-Ming
Liu, Yue
Bu, Tegeleqi
Zhang, Qingy
Wang, Yong-An
Zhao, Jing
Luo, Yuan
author_facet Wang, Li-Fang
Sun, Yang-Yang
Pan, Qian
Yin, Yi-Qing
Tian, Xiao-Ming
Liu, Yue
Bu, Tegeleqi
Zhang, Qingy
Wang, Yong-An
Zhao, Jing
Luo, Yuan
author_sort Wang, Li-Fang
collection PubMed
description Lung ischemia-reperfusion (IR) injury is induced by pulmonary artery occlusion and reperfusion. Lung IR injury commonly happens after weaning from extracorporeal circulation, lung transplantation, and pulmonary thromboendarterectomy; it is a lethal perioperative complication. A definite therapeutic intervention remains to be determined. It is known that the enzyme activity of angiotensin-converting enzyme 2 (ACE2) is critical in maintaining pulmonary vascular tone and epithelial integrity. In a noxious environment to the lungs, inactivation of ACE2 is mainly due to a disintegrin and metalloprotease 17 (ADAM17) protein-mediated ACE2 shedding. Thus, we assumed that protection of local ACE2 in the lung against ADAM17-mediated shedding would be a therapeutic target for lung IR injury. In this study, we established both in vivo and in vitro models to demonstrate that the damage degree of lung IR injury depends on the loss of ACE2 and ACE2 enzyme dysfunction in lung tissue. Treatment with ACE2 protectant diminazen aceturate (DIZE) maintained higher ACE2 enzyme activity and reduced angiotensin II, angiotensin type 1 receptor, and ADAM17 levels in the lung tissue. Concurrently, DIZE-inhibited oxidative stress and nitrosative stress via p38MAPK and NF-κB pathways consequently reduced release of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β. The underlying molecular mechanism of DIZE contributed to its protective effect against lung IR injury and resulted in the improvement of oxygenation index and ameliorating pulmonary pathological damage. We concluded that DIZE protects the lungs from IR injury via inhibition of ADAM17-mediated ACE2 shedding.
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spelling pubmed-85461182021-10-27 Diminazen Aceturate Protects Pulmonary Ischemia-Reperfusion Injury via Inhibition of ADAM17-Mediated Angiotensin-Converting Enzyme 2 Shedding Wang, Li-Fang Sun, Yang-Yang Pan, Qian Yin, Yi-Qing Tian, Xiao-Ming Liu, Yue Bu, Tegeleqi Zhang, Qingy Wang, Yong-An Zhao, Jing Luo, Yuan Front Pharmacol Pharmacology Lung ischemia-reperfusion (IR) injury is induced by pulmonary artery occlusion and reperfusion. Lung IR injury commonly happens after weaning from extracorporeal circulation, lung transplantation, and pulmonary thromboendarterectomy; it is a lethal perioperative complication. A definite therapeutic intervention remains to be determined. It is known that the enzyme activity of angiotensin-converting enzyme 2 (ACE2) is critical in maintaining pulmonary vascular tone and epithelial integrity. In a noxious environment to the lungs, inactivation of ACE2 is mainly due to a disintegrin and metalloprotease 17 (ADAM17) protein-mediated ACE2 shedding. Thus, we assumed that protection of local ACE2 in the lung against ADAM17-mediated shedding would be a therapeutic target for lung IR injury. In this study, we established both in vivo and in vitro models to demonstrate that the damage degree of lung IR injury depends on the loss of ACE2 and ACE2 enzyme dysfunction in lung tissue. Treatment with ACE2 protectant diminazen aceturate (DIZE) maintained higher ACE2 enzyme activity and reduced angiotensin II, angiotensin type 1 receptor, and ADAM17 levels in the lung tissue. Concurrently, DIZE-inhibited oxidative stress and nitrosative stress via p38MAPK and NF-κB pathways consequently reduced release of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β. The underlying molecular mechanism of DIZE contributed to its protective effect against lung IR injury and resulted in the improvement of oxygenation index and ameliorating pulmonary pathological damage. We concluded that DIZE protects the lungs from IR injury via inhibition of ADAM17-mediated ACE2 shedding. Frontiers Media S.A. 2021-10-12 /pmc/articles/PMC8546118/ /pubmed/34712133 http://dx.doi.org/10.3389/fphar.2021.713632 Text en Copyright © 2021 Wang, Sun, Pan, Yin, Tian, Liu, Bu, Zhang, Wang, Zhao and Luo. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Wang, Li-Fang
Sun, Yang-Yang
Pan, Qian
Yin, Yi-Qing
Tian, Xiao-Ming
Liu, Yue
Bu, Tegeleqi
Zhang, Qingy
Wang, Yong-An
Zhao, Jing
Luo, Yuan
Diminazen Aceturate Protects Pulmonary Ischemia-Reperfusion Injury via Inhibition of ADAM17-Mediated Angiotensin-Converting Enzyme 2 Shedding
title Diminazen Aceturate Protects Pulmonary Ischemia-Reperfusion Injury via Inhibition of ADAM17-Mediated Angiotensin-Converting Enzyme 2 Shedding
title_full Diminazen Aceturate Protects Pulmonary Ischemia-Reperfusion Injury via Inhibition of ADAM17-Mediated Angiotensin-Converting Enzyme 2 Shedding
title_fullStr Diminazen Aceturate Protects Pulmonary Ischemia-Reperfusion Injury via Inhibition of ADAM17-Mediated Angiotensin-Converting Enzyme 2 Shedding
title_full_unstemmed Diminazen Aceturate Protects Pulmonary Ischemia-Reperfusion Injury via Inhibition of ADAM17-Mediated Angiotensin-Converting Enzyme 2 Shedding
title_short Diminazen Aceturate Protects Pulmonary Ischemia-Reperfusion Injury via Inhibition of ADAM17-Mediated Angiotensin-Converting Enzyme 2 Shedding
title_sort diminazen aceturate protects pulmonary ischemia-reperfusion injury via inhibition of adam17-mediated angiotensin-converting enzyme 2 shedding
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8546118/
https://www.ncbi.nlm.nih.gov/pubmed/34712133
http://dx.doi.org/10.3389/fphar.2021.713632
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