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Obstructive Lung Diseases: COPD: Etiology |

The Angiotensin-Converting Enzyme 2/Angiotensin (1-7)/Mas Axis Protects Against Cigarette Smoke-Induced Apoptosis of Alveolar Epithelial Cells by Inhibiting the NOX4-Derived ROS-Mediated JNK-Bax-Caspase3 Pathway FREE TO VIEW

Ting Li, MD; Xu Li, PhD; Yan Chen, MD; Miaoxia Pan, MD; Minzhou Zhang, MD; Ying Meng, PhD
Author and Funding Information

Department of Intensive Care Unit (ICU), Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou, China


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2016;149(4_S):A349. doi:10.1016/j.chest.2016.02.364
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SESSION TITLE: COPD: Etiology

SESSION TYPE: Original Investigation Poster

PRESENTED ON: Saturday, April 16, 2016 at 11:45 AM - 12:45 PM

PURPOSE: Chronic obstructive pulmonary disease (COPD) is a prevalent smoking-related disease for which no disease altering therapies currently exist. The angiotensin-converting enzyme 2 (ACE2)/angiotensin (1-7) [Ang(1-7)]/Mas axis, which counteracts the angiotensin-converting enzyme (ACE)/angiotensin II (AngII)/angiotensin II type 1 receptor (AT1R) axis, has been shown to attenuate cigarette smoke-induced lung injury. Nevertheless, the exact molecular mechanism remains unclear. The present study evaluated the protective effects of the ACE2/Ang(1-7)/Mas axis on cigarette smoke-induced apoptosis of alveolar epithelial cells by inhibiting the NOX4-derived ROS-mediated JNK-Bax-caspase3 pathway.

METHODS:In vivo, male Sprague Dawley rats was intratracheally administered with lentiviral packaged ACE2 cDNA or constantly infused with Ang(1-7). Two weeks later, animals was exposure to CS by cigarettes using a smoking machine for 8 weeks. In vitro, A549 human lung carcinoma cells were pretreated with compounds that block the activities of NOX4 (diphenylene iodonium DPI), ROS (N-acetylcysteine NAC), JNK (SP600125) and Mas (A779) before exposure to cigarette smoke extract (CSE) or Ang(1-7). The A549 human lung carcinoma cells were infected with lentivirus-mediated ACE2 before exposure to CSE.

RESULTS:In vivo, constant infusion with Ang(1-7) or intratracheal instillation with lenti-ACE2 alleviated cigarette smoke-induced apoptosis of alveolar epithelial cells and inhibited the JNK-Bax-caspase3 pathway by reducing NOX4-derived ROS. In vitro, CSE induced apoptosis of alveolar epithelial cells and the activities of the NOX4-derived ROS-mediated JNK-Bax-caspase3 pathway in a dose-independent manner. These changes were attenuated by pretreatment with DPI, NAC and SP600125. Furthermore, Ang(1-7) and lentivirus-mediated ACE2 inhibited CSE-induced NOX4-derived ROS-mediated JNK-Bax-caspase3 pathway, thereby supressing apoptosis of alveolar epithelial cells, which could be reversed by the Mas inhibitor, A779.

CONCLUSIONS: The ACE2/Ang(1-7) /Mas axis protects against cigarette smoke-induced apoptosis of alveolar epithelial cells by inhibiting the NOX4-derived ROS-mediated JNK-Bax-caspase3 pathway.

CLINICAL IMPLICATIONS: The anti-apoptotic effects of Ang(1-7) make the heptapeptide a candidate for a therapeutic target in humans with chronic obstructive pulmonary disease.

DISCLOSURE: Ting Li: University grant monies: ownership interest Xu Li: University grant monies: ownership interest Yan Chen: University grant monies: ownership interest Miaoxia Pan: University grant monies: ownership interest Minzhou Zhang: University grant monies: ownership interest Ying Meng: University grant monies: ownership interest

The anti-apoptotic effects of Ang(1-7) make the heptapeptide a candidate for a therapeutic target in humans with chronic obstructive pulmonary disease.


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