Overexpression of the SARS‐CoV‐2 receptor ACE2 is induced by cigarette smoke in bronchial and alveolar epithelia

Abstract

Angiotensin‐converting enzyme 2 (ACE2) has been identified as the functional receptor of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and a target for disease prevention. However, the relationship between ACE2 expression and its clinical implications in SARS‐CoV‐2 pathogenesis remain unknown. Here, we explored the location and expression of ACE2, and its correlation with gender, age and cigarette smoke (CS), in a CS‐exposed mouse model and 224 non‐malignant lung tissues (125 non‐smokers, 81 current smokers and 18 ex‐smokers) by immunohistochemistry. Moreover, the correlations of ACE2 with CS‐induced oxidative stress‐related markers, hypoxia inducible factor‐1α (HIF‐1α), inducible nitric oxide synthase (iNOS), and 4‐hydroxynonenal (4‐HNE) were investigated. Chromatin immunoprecipitation and luciferase reporter assays identified the cause of ACE2 overexpression in human primary lung epithelial cells. We demonstrated that ACE2 was predominantly overexpressed on the apical surface of bronchial epithelium, while reduced in alveolar epithelium, owing to the dramatically decreased abundance of alveolar type II pneumocytes in CS‐exposed mouse lungs. Consistent with this, ACE2 was primarily significantly overexpressed in human bronchial and alveolar epithelial cells in smokers regardless of age or gender. Decreased ACE2 expression was observed in bronchial epithelial cells from ex‐smokers compared with current‐smokers, especially in those who had ceased smoking for more than 10 years. Moreover, ACE2 expression was positively correlated with the levels of HIF‐1α, iNOS, and 4‐HNE in both mouse and human bronchioles. The results were further validated using a public available dataset from The Cancer Genome Atlas (TCGA) and our previous integrated data from Affymetrix U133 Plus2.0 microarray (AE‐meta). Finally, our results showed that HIF‐1α transcriptionally upregulates ACE2 expression. Our results indicate that smoking‐induced ACE2 overexpression in the apical surface of bronchial epithelial cells provide a route by which SARS‐CoV‐2 enters host cells, which supports clinical relevance in attenuating the potential transmission risk of COVID‐19 in smoking populations by smoking cessation. This article is protected by copyright. All rights reserved.

Hypoxia reduces cell attachment of SARS-CoV-2 spike protein by modulating the expression of ACE2, neuropilin-1, syndecan-1 and cellular heparan sulfate

“…Moreover, hypoxia reduced the infection rate of Vero E6 cells by pseudotyped SARS-CoV-2 lentiviral particles. The observed reduction of ACE2 protein level contrasts with the early transcriptional increase of this gene, a well-documented observation that likely results from the binding of the hypoxia inducible factor (HIF) transcription factors to hypoxia response elements on the ACE2 promoter (Liu et al, 2020). The observed discrepancy at the RNA vs. protein ACE2 levels might be explained by protein degradation, cleavage (Heurich et al, 2014) or timedependent adaptation to hypoxia.…”

Comparative analysis of ACE2 protein expression in rodent, non-human primate, and human respiratory tract at baseline and after injury: A conundrum for COVID-19 pathogenesis

“…This result differs from significant ACE2 upregulation reported by Liu et al . in human lung specimens of cigarette smokers and may be explained by the relative lack of chronicity in the NHP model [ 44 ]. However, consistent with our findings, images of human airways from non-smokers in the paper by Liu et al .…”

Diesel Particulate Matter 2.5 Induces Epithelial-to-Mesenchymal Transition and Upregulation of SARS-CoV-2 Receptor during Human Pluripotent Stem Cell-Derived Alveolar Organoid Development

“…Recent epidemiological investigations proposed a potential relationship between PM2.5 concentrations and the susceptibility severity of SARS-CoV-2 [ 31 , 32 , 33 , 34 ], which might be closely associated with altered expression of ACE2 by chronic exposure to fine PM2.5 [ 35 ]. Recently, computational analysis of sequencing data from patients with chronic lung diseases revealed that dysregulation of androgen, hypoxia-inducible factor 1-alpha, interferon, and IL-6 cytokine pathways is associated with upregulation of ACE2 and SARS-Cov-2 severity [ 36 , 37 , 38 , 39 , 40 ]. To the best of our knowledge, this is the first study reporting the transcriptional and translational upregulation of ACE2 in hPSC-derived AECs and 3D AOs by exposure to dPM2.5.…”