Hypoxia, HIF-1α, and COVID-19: from pathogenic factors to potential therapeutic targets

• Published in: Acta pharmacologica Sinica Vol. 41; no. 12; pp. 1539 - 1546
• Main Authors: Serebrovska, Zoya O., Chong, Elisa Y., Serebrovska, Tetiana V., Tumanovska, Lesia V., Xi, Lei
• Format: Journal Article
• Language: English
• Published: Singapore Springer Singapore 01-12-2020; Nature Publishing Group
• Subjects: ACE2; Angiotensin; Angiotensin-converting enzyme 2; Animals; Antiviral agents; Antiviral Agents - pharmacology; Biomedical and Life Sciences; Biomedicine; Coronaviridae; Coronaviruses; COVID-19; COVID-19 - drug therapy; COVID-19 - physiopathology; COVID-19 - virology; Cytokine Release Syndrome - virology; Cytokine storm; Cytokines; Drug Development; Drug Repositioning; Drug therapy; Gas exchange; Humans; Hydroxychloroquine; Hypoxia; Hypoxia - drug therapy; Hypoxia - virology; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factor 1a; Immunology; Inflammation; Internal Medicine; Lethality; Medical Microbiology; Molecular modelling; Molecular Targeted Therapy; Pandemics; Peptidyl-dipeptidase A; Pharmacology/Toxicology; Public health; Respiratory distress syndrome; Review; Review Article; SARS-CoV-2 - isolation & purification; SARS-CoV-2 - pathogenicity; Serine; Severe acute respiratory syndrome coronavirus 2; Vaccine; COVID-19; cytokine; hypoxia; ACE2; hypoxic conditioning; HIF-1α
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/s41401-020-00554-8

The pandemic of coronavirus disease 2019 (COVID-19) and its pathogen, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have become the greatest current threat to global public health. The highly infectious SARS-CoV-2 virus primarily attacks pulmonary tissues and impairs gas exchange leading to acute respiratory distress syndrome (ARDS) and systemic hypoxia. The current pharmacotherapies for COVID-19 largely rely on supportive and anti-thrombi treatment and the repurposing of antimalarial and antiviral drugs such as hydroxychloroquine and remdesivir. For a better mechanistic understanding of COVID-19, our present review focuses on its primary pathophysiologic features: hypoxia and cytokine storm, which are a prelude to multiple organ failure and lethality. We discussed a possible link between the activation of hypoxia inducible factor 1α (HIF-1α) and cell entry of SARS-CoV-2, since HIF-1α is shown to suppress the angiotensin-converting enzyme 2 (ACE2) receptor and transmembrane protease serine 2 (TMPRSS2) and upregulate disintegrin and metalloproteinase domain-containing protein 17 (ADAM17). In addition, the protein targets of HIF-1α are involved with the activation of pro-inflammatory cytokine expression and the subsequent inflammatory process. Furthermore, we hypothesized a potential utility of so-called “hypoxic conditioning” to activate HIF-1α-induced cytoprotective signaling for reduction of illness severity and improvement of vital organ function in patients with COVID-19. Taken together, we would propose further investigations into the hypoxia-related molecular mechanisms, from which novel targeted therapies can be developed for the improved management of COVID-19.