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

Recent work from this laboratory demonstrated potent inhibition of apoptosis in human alveolar epithelial cells (AECs) by the angiotensin-converting enzyme inhibitor captopril [B. D. Uhal, C. Gidea, R. Bargout, A. Bifero, O. Ibarra-Sunga, M. Papp, K. Flynn, and G. Filippatos. Am. J. Physiol. 275 ( Lung Cell. Mol. Physiol. 19): L1013–L1017, 1998]. On this basis, we hypothesized that apoptosis in this cell type might be induced by angiotensin II (ANG II) through its interaction with the ANG II receptor. Purified ANG II induced dose-dependent apoptosis in both the human AEC-derived A549 cell line and in primary type II pneumocytes isolated from adult Wistar rats as detected by nuclear and chromatin morphology, caspase-3 activity, and increased binding of annexin V. Apoptosis also was induced in primary rat AECs by purified angiotensinogen. The nonselective ANG II-receptor antagonist saralasin completely abrogated both ANG II- and angiotensinogen-induced apoptosis at a concentration of 50 μg/ml. With RT-PCR, both cell types expressed the ANG II-receptor subtypes 1 and 2 and angiotensin-converting enzyme (ACE). The nonthiol ACE inhibitor lisinopril blocked apoptosis induced by angiotensinogen, but not apoptosis induced by purified ANG II. These data demonstrate the presence of a functional ANG II-dependent pathway for apoptosis in human and rat AECs and suggest a role for the ANG II receptor and ACE in the induction of AEC apoptosis in vivo.

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Hypoxia induces expression of angiotensin‐converting enzyme II in alveolar epithelial cells: Implications for the pathogenesis of acute lung injury in COVID‐19

Physiological Reports ◽

10.14814/phy2.14854 ◽

2021 ◽

Vol 9 (9) ◽

Author(s):

Anne Sturrock ◽

Elizabeth Zimmerman ◽

My Helms ◽

Theodore G. Liou ◽

Robert Paine

Keyword(s):

Acute Lung Injury ◽

Epithelial Cells ◽

Lung Injury ◽

Angiotensin Converting Enzyme ◽

Alveolar Epithelial Cells ◽

Converting Enzyme ◽

Alveolar Epithelial

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Identification of the SARS-CoV-2 Entry Receptor ACE2 as a Direct Target for Transcriptional Repression by Miz1

Frontiers in Immunology ◽

10.3389/fimmu.2021.648815 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jing Yang ◽

Edith A. Perez ◽

Changchun Hou ◽

Pin Zhang ◽

Michelle Van Scoyk ◽

...

Keyword(s):

Epithelial Cells ◽

Angiotensin Converting Enzyme ◽

Cigarette Smoke ◽

Lung Epithelial Cells ◽

Cigarette Smoke Exposure ◽

Chronic Obstructive ◽

Converting Enzyme ◽

Angiotensin Converting Enzyme 2 ◽

Copd Patients ◽

Lung Epithelial

Multiple lines of evidence have demonstrated that cigarette smoke or Chronic Obstructive Pulmonary Disease upregulates angiotensin-converting enzyme 2, the cellular receptor for the entry of the severe acute respiratory syndrome coronavirus 2, which predisposes individuals to develop severe Coronavirus disease 2019. The reason for this observation is unknown. We recently reported that the loss of function of Miz1 in the lung epithelium in mice leads to a spontaneous COPD-like phenotype, associated with upregulation of angiotensin-converting enzyme 2. We also reported that cigarette smoke exposure downregulates Miz1 in lung epithelial cells and in mice, and Miz1 is also downregulated in the lungs of COPD patients. Here, we provide further evidence that Miz1 directly binds to and represses the promoter of angiotensin-converting enzyme 2 in mouse and human lung epithelial cells. Our data provide a potential molecular mechanism for the upregulation of angiotensin-converting enzyme 2 observed in smokers and COPD patients, with implication in severe Coronavirus disease 2019.

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Traffic-derived particulate matter and angiotensin-converting enzyme 2 expression in human airway epithelial cells

10.1101/2020.05.15.097501 ◽

2020 ◽

Cited By ~ 4

Author(s):

L Miyashita ◽

G Foley ◽

S Semple ◽

J Grigg

Keyword(s):

Particulate Matter ◽

Epithelial Cells ◽

Angiotensin Converting Enzyme ◽

Cigarette Smoke ◽

A549 Cells ◽

Cigarette Smoke Extract ◽

Airway Epithelial ◽

Converting Enzyme ◽

Angiotensin Converting Enzyme 2 ◽

Human Airway

AbstractBackgroundThe mechanism for the association between traffic-derived particulate matter less than 10 microns (PM10) and cases of COVID-19 disease reported in epidemiological studies is unknown. To infect cells, the spike protein of SARS-CoV-2 interacts with angiotensin-converting enzyme 2 (ACE2) on host airway cells. Increased ACE2 expression in lower airway cells in active smokers, suggests a potential mechanism whereby PM10 increases vulnerability to COVID-19 disease.ObjectiveTo assess the effect of traffic-derived PM10 on human airway epithelial cell ACE2 expression in vitro.MethodsPM10 was collected from Marylebone Road (London) using a kerbside impactor. A549 and human primary nasal epithelial cells were cultured with PM10 for 2 h, and ACE2 expression (median fluorescent intensity; MFI) assessed by flow cytometry. We included cigarette smoke extract as a putative positive control. Data were analysed by either Mann-Whitney test, or Kruskal-Wallis with Dunn’s multiple comparisons test.ResultsPM10 at 10 μg/mL, and 20 μg/mL increased ACE2 expression in A549 cells (P<0.05, 0.01 vs. medium control, respectively). Experiments using a single PM10 concentration (10 μg/mL), found increased ACE2 expression in both A549 cells (control vs. PM10, median (IQR) MFI; 470 (0.1 to 1114) vs 6217 (5071 to 8506), P<0.01), and in human primary epithelial cells (0 (0 to 591) vs. 4000 (2610 to 7853), P<0.05). Culture of A549 cells with 5% cigarette smoke extract increased ACE2 expression (n=4, 0 (0 to 28) vs. 9088 (7557 to 15831, P<0.05).ConclusionTraffic-related PM10 increases the expression of the receptor for SARS-CoV-2 in human respiratory epithelial cells.

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Alveolar epithelial cells type II show a high sensitivity to cigarette smoke extract

Pneumologie ◽

10.1055/s-0034-1376780 ◽

2014 ◽

Vol 68 (06) ◽

Author(s):

S Seehase ◽

B Baron-Luehr ◽

C Kugler ◽

E Vollmer ◽

T Goldmann

Keyword(s):

Epithelial Cells ◽

Cigarette Smoke ◽

High Sensitivity ◽

Cigarette Smoke Extract ◽

Alveolar Epithelial Cells ◽

Type Ii ◽

Alveolar Epithelial

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Senescence associated long non-coding RNA 1 regulates cigarette smoke-induced senescence of type II alveolar epithelial cells through sirtuin-1 signaling

Journal of International Medical Research ◽

10.1177/0300060520986049 ◽

2021 ◽

Vol 49 (2) ◽

pp. 030006052098604

Author(s):

Dong Yuan ◽

Yuanshun Liu ◽

Mengyu Li ◽

Hongbin Zhou ◽

Liming Cao ◽

...

Keyword(s):

Epithelial Cells ◽

Cigarette Smoke ◽

Alveolar Epithelial Cell ◽

Alveolar Epithelial Cells ◽

Lung Epithelial Cells ◽

Sirtuin 1 ◽

Type Ii ◽

Alveolar Epithelial ◽

Non Coding Rna ◽

Long Non Coding Rna

Objective The primary aim of our study was to explore the mechanisms through which long non-coding RNA (lncRNA)-mediated sirtuin-1 (SIRT1) signaling regulates type II alveolar epithelial cell (AECII) senescence induced by a cigarette smoke-media suspension (CSM). Methods Pharmacological SIRT1 activation was induced using SRT2104 and senescence-associated lncRNA 1 (SAL-RNA1) was overexpressed. The expression of SIRT1, FOXO3a, p53, p21, MMP-9, and TIMP-1 in different groups was detected by qRT-PCR and Western blotting; the activity of SA-β gal was detected by staining; the binding of SIRT1 to FOXO3a and p53 gene transcription promoters was detected by Chip. Results We found that CSM increased AECII senescence, while SAL-RNA1 overexpression and SIRT1 activation significantly decreased levels of AECII senescence induced by CSM. Using chromatin immunoprecipitation, we found that SIRT1 bound differentially to transcriptional complexes on the FOXO3a and p53 promoters. Conclusion Our results suggested that lncRNA-SAL1-mediated SIRT1 signaling reduces senescence of AECIIs induced by CSM. These findings suggest a new therapeutic target to limit the irreversible apoptosis of lung epithelial cells in COPD patients.

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Regulation of the Expression of SARS-CoV-2 Receptor Angiotensin-Converting Enzyme 2 in Nasal Mucosa

American Journal of Rhinology and Allergy ◽

10.1177/19458924211027798 ◽

2021 ◽

pp. 194589242110277

Author(s):

Tetsuji Takabayashi ◽

Kanako Yoshida ◽

Yoshimasa Imoto ◽

Robert P. Schleimer ◽

Shigeharu Fujieda

Keyword(s):

Epithelial Cells ◽

Angiotensin Converting Enzyme ◽

Nasal Mucosa ◽

Japanese Cedar ◽

Airway Epithelial Cells ◽

Airway Epithelial ◽

Converting Enzyme ◽

Angiotensin Converting Enzyme 2 ◽

Japanese Cedar Pollen ◽

Cedar Pollen

Background Coronavirus disease 2019 (COVID-19) has caused a global pandemic. Higher expression of the virus receptor angiotensin-converting enzyme 2 (ACE2) in the nasal mucosa may be associated with high transmissibility and asymptomatic infection. In COVID-19, the elucidation of the determinants of ACE2 expression at nasal tissue level is crucial. The development of strategies to downregulate ACE2 expression in nasal epithelial cells might reduce transmission and be useful as a novel therapeutic approach. Objective To verify ACE2 expression in the nasal mucosa of patients with seasonal allergic rhinitis induced by Japanese cedar pollen (SAR-JCP) and chronic rhinosinusitis with nasal polyp (CRSwNP) and to examine the effects of short-chain fatty acids (SCFAs) on ACE2 expression in airway epithelial cells. Methods We assessed ACE2 expression in the nasal mucosa of control subjects, patients with SAR-JCP, and those with CRSwNP using real-time polymerase chain reaction. We also quantified ACE2 gene expression in cultured airway epithelial cells. Results Although ACE2 expression was greatly increased in a few patients with SAR-JCP during the Japanese cedar pollen season, mean levels were not significantly increased. ACE2 mRNA expression was significantly decreased in nasal polyp tissue from patients with chronic rhinosinusitis compared with the expression in that from control subjects. SCFAs generated by gastrointestinal microbiota significantly reduced resting ACE2 expression in cultured airway epithelial cells. SCFAs also significantly suppressed the dsRNA-dependent upregulation of ACE2 expression in airway epithelial cells. Conclusion Inflammatory endotype affects ACE2 expression in the nasal mucosa and influences susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In particular, type 2 inflammation could downregulate ACE2 expression in the nasal mucosa and reduces susceptibility to SARS-CoV-2 in patients with CRSwNP. Although in vivo experiments are required, administration of SCFAs to the nasal cavity might be worthy of consideration as a preventative or therapeutic strategy for the early-stage COVID-19.

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Abrogation of ER stress-induced apoptosis of alveolar epithelial cells by angiotensin 1–7

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00001.2013 ◽

2013 ◽

Vol 305 (1) ◽

pp. L33-L41 ◽

Cited By ~ 29

Author(s):

Bruce D. Uhal ◽

Hang Nguyen ◽

MyTrang Dang ◽

Indiwari Gopallawa ◽

Jing Jiang ◽

...

Keyword(s):

Epithelial Cells ◽

Er Stress ◽

Cathepsin D ◽

Primary Cultures ◽

A549 Cells ◽

Surfactant Protein ◽

Alveolar Epithelial Cells ◽

Alveolar Epithelial ◽

Induced Apoptosis ◽

Jnk Activation

Earlier work showed that apoptosis of alveolar epithelial cells (AECs) in response to endogenous or xenobiotic factors is regulated by autocrine generation of angiotensin (ANG) II and its counterregulatory peptide ANG1–7. Mutations in surfactant protein C (SP-C) induce endoplasmic reticulum (ER) stress and apoptosis in AECs and cause lung fibrosis. This study tested the hypothesis that ER stress-induced apoptosis of AECs might also be regulated by the autocrine ANGII/ANG1–7 system of AECs. ER stress was induced in A549 cells or primary cultures of human AECs with the proteasome inhibitor MG132 or the SP-C BRICHOS domain mutant G100S. ER stress activated the ANGII-generating enzyme cathepsin D and simultaneously decreased the ANGII-degrading enzyme ACE-2, which normally generates the antiapoptotic peptide ANG1–7. TAPI-2, an inhibitor of ADAM17/TACE, significantly reduced both the activation of cathepsin D and the loss of ACE-2. Apoptosis of AECs induced by ER stress was measured by assays of mitochondrial function, JNK activation, caspase activation, and nuclear fragmentation. Apoptosis induced by either MG132 or the SP-C BRICHOS mutant G100S was significantly inhibited by the ANG receptor blocker saralasin and was completely abrogated by ANG1–7. Inhibition by ANG1–7 was blocked by the specific mas antagonist A779. These data show that ER stress-induced apoptosis is mediated by the autocrine ANGII/ANG1–7 system in human AECs and demonstrate effective blockade of SP-C mutation-induced apoptosis by ANG1–7. They also suggest that therapeutic strategies aimed at administering ANG1–7 or stimulating ACE-2 may hold potential for the management of ER stress-induced fibrotic lung disorders.

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