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Review
. 2021 Nov 7;10(11):3067.
doi: 10.3390/cells10113067.

Endothelial Dysfunction through Oxidatively Generated Epigenetic Mark in Respiratory Viral Infections

Spiros Vlahopoulos  1 , Ke Wang  2   3 , Yaoyao Xue  2   3 , Xu Zheng  2   3 , Istvan Boldogh  2 , Lang Pan  2   4
Affiliations
Review

Endothelial Dysfunction through Oxidatively Generated Epigenetic Mark in Respiratory Viral Infections

Spiros Vlahopoulos et al. Cells. .

Abstract

The bronchial vascular endothelial network plays important roles in pulmonary pathology during respiratory viral infections, including respiratory syncytial virus (RSV), influenza A(H1N1) and importantly SARS-Cov-2. All of these infections can be severe and even lethal in patients with underlying risk factors.A major obstacle in disease prevention is the lack of appropriate efficacious vaccine(s) due to continuous changes in the encoding capacity of the viral genome, exuberant responsiveness of the host immune system and lack of effective antiviral drugs. Current management of these severe respiratory viral infections is limited to supportive clinical care. The primary cause of morbidity and mortality is respiratory failure, partially due to endothelial pulmonary complications, including edema. The latter is induced by the loss of alveolar epithelium integrity and by pathological changes in the endothelial vascular network that regulates blood flow, blood fluidity, exchange of fluids, electrolytes, various macromolecules and responses to signals triggered by oxygenation, and controls trafficking of leukocyte immune cells. This overview outlines the latest understanding of the implications of pulmonary vascular endothelium involvement in respiratory distress syndrome secondary to viral infections. In addition, the roles of infection-induced cytokines, growth factors, and epigenetic reprogramming in endothelial permeability, as well as emerging treatment options to decrease disease burden, are discussed.

Keywords: SARS-Cov-2; endothelial cells; gene expression; influenza H1N1; oxidative stress; pulmonary edema; respiratory distress syndrome; respiratory syncytial virus.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Cellular sources of ROS in respiratory viral infections. Activation of receptors liganded by RSV, influenza and SARS-CoV-2 envelope proteins and the recognition of viral PAMPs by intracellular sensors (NLRs, TLRs) trigger signaling pathways, leading to activation of oxidoreductases located in cell membranes, endoplasmic reticulum, peroxisomes, and mitochondria. NADPH oxidases (NOXs) are the primary enzyme complexes in nearly all cell types, particularly in granulocytes and macrophages, along with oxidoreductases in mitochondrial complex I and II, which partially oxidize oxygen molecules to generate superoxide anion (O2•−). O2•− via Fenton and/or Haber-Weiss reactions are converted into hydroxyl radical (•OH). The highly reactive •OH reacts with proteins, lipids and DNA. ROS themselves, but particularly peroxidation of polyunsaturated fatty acids, trigger nuclear translocation of nuclear factor erythroid 2-related factor 2 (NRF2), which heterodimerizes with small musculoaponeurotic fibrosarcoma (MAF) transcription factor and binds the cis-acting enhancer antioxidant response element (ARE), leading to the expression of antioxidant enzymes, including Cu/Zn-superoxide dismutase (SOD1), glutathione peroxidases (GPXs) and catalase (CAT). However, in RSV and SARS-CoV-2infected cells and lungs there is a progressive decrease in levels of NRF2 via increased protein ubiquitination and its degradation through a proteasomal pathway [93,99,100,101]. Although ROS generation in RSV, SARS-CoV-2 infected cells is similar, it seems that NRF2 primarily modifies influenza A entry and replication [102]. In addition to the above-described pathways, activated monocytes and polymorphonuclear cells, in particular, neutrophils, have been shown to produce ROS. Abbreviations: NLR, nucleotide-binding oligomerization domain-like receptors; TLR, TOLL-like receptors, PAMP, pathogen-associated molecular patterns; NOX, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase; ER, endoplasmic reticulum.
Figure 2
Figure 2
Models for OGG1-8-oxoGua-dependent gene expression. (A) Viral infection-induced ROS or those generated by cytokine exposure oxidatively modify guanine to 8-oxoGua and inactivate OGG1′ glycosylase activity by reversible oxidation at cysteine residues (cysteine-sulfenic acid). Oxidatively disabled OGG1 flips 8-oxoGua into its active-site pocket, interacts with the opposing cytosine and results in the conformational change of the DNA helix, which favors TFs DNA occupancy. (B) OGG1-8-oxoGua driven gene expression under hypoxic conditions. Guanines in gene promoters with G-quadruplexes are highly sensitive to ROS and are oxidized to 8-oxoGua under tissue hypoxia, caused by SARS-CoV-2, RSV, or H1N1 infections during pneumonia. OGG1 excises 8-oxoGua and generates an AP-site a substrate for APE1. APE1 binding leads to melting of the guanine duplex and stalls because of the non-canonical structure. Stalled APE1 increases transcription factor loading on the DNA via transient cooperative binding via conformational change of the helix. APE1, via its interacting domain, interacts with TFs (e.g., HIF1-α, STAT3, and CBP/p300) to modulate their redox state and promote both their binding to cis elements and gene expression. (C) OGG1-dependent transcription initiated by estrogens and its nuclear receptor. Estrogen (17β-estradiol; E2) binding to estrogen receptor alpha (ERα) results in demethylation of histone H3 lysine 9 (H3K9me2) via lysine-specific histone demethylase (LSD1; a flavin-dependent amine oxidase). Histone demethylation leads to a focal superoxide anion, hydroxyl radical generation and induces site-specific oxidation of guanine to 8-oxoGua. The latter is recognized and excised by OGG1 and via its AP-lyase activity cleave into the DNA strand generating the AP-site. The strand gap is recognized by topoisomerase II beta (topo IIb), which results in DNA structural changes in the chromatin allowing efficient assembly of transcriptional machinery and gene expression. Such scenarios are relevant to acute lung injury and SARS-CoV-2 infection capacity [138,139]. Similarly, LSD1-dependent DNA oxidation and OGG1 recruitment was needed for gene expression driven by TNFα, retinoic acid, and androgen exposure of cells [140,141,142]. Abbreviations: AP-site, apurinic/apyrimidinic site; APE-1, apurinic/apyrimidinic endonuclease 1; FAD, flavin adenine dinucleotide; FADH2, reduced flavin adenine dinucleotide; LSD1, flavin-dependent amine oxidase 1, 3-OH, 3-terminal hydroxyl; 5′-dRP, 5-terminal deoxyribose-phosphate.
Figure 3
Figure 3
Proposed depiction of endothelial dysfunction by ROS in respiratory virus-infected airways and potential therapeutic intervention. (A) Oxidative modification to the heterocyclic DNA base guanine(s) in gene regulatory sequences is considered an epigenetic mark that is recognized by the “reader” OGG1, leading assembly of transcriptional complex and dysregulated gene expression. Consequences are pulmonary edema, congestion, respiratory failure in patients with risk factor(s). (B) Inhibition of OGG1′ interaction with epigenetic mark decreases extent of inflammation and manifestation of endothelial dysfunction. TH5487, and SUO268, OGG1 specific inhibitors; BRD4, bromodomain-containing protein 4; CDK9, cyclin-dependent kinase 9; p50-p65, nuclear factor kappa B; CBP/p300, RNA pol II, RNA polymerase II.
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