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

Abstract

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-1αinduced 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.

Can efficient stimulation of myogenic microcirculatory oscillations by transient ischemia predict low incidence of COVID-19 infection?

“…There are numerous reports indicating the protective effects of HIF-1α against epithelial injury via the hypoxic preconditioning mechanism ( Olson et al, 2011 ; Serebrovska et al, 2020 ). Such protection can minimize the loss of epithelial barrier integrity by oxidative stress.…”

SARS-CoV-2 ORF6 disturbs nucleocytoplasmic trafficking to advance the viral replication

“…Moreover, the another GTEx analysis indicated that the levels of KPNA2 in the lungs tend to be lower in Asians than in other genetic ancestries, although further data need to be required to make a definite conclusion, since the sample size for the Asian group is smaller than that of the other groups. Since hypoxia has been recognized as a pathogenic factor in COVID-19 patients 43, 44 , we suspect that ORF6 might impair the nuclear import of HIF-1α, which is required for the response to hypoxia, to affect lung cell functions in the COVID-19 patients, so that the lung oxygen levels cannot be maintained appropriately. Thus, the downregulation of importin α1 may accelerate the replication of the virus in the lungs, in particular in older individuals.…”

SARS-CoV-2, Hypoxia, and Calcium Signaling: The Consequences and Therapeutic Options

“…The hypoxic response is very complex as it regulates many signal transduction pathways and expression of genes. Recently, it has been reported that the novel SARS-CoV-2 causes hypoxia, 1 and earlier investigation has supported that hypoxia leads to alteration in Ca 2+ cell signaling. 2 During hypoxia, an increase in intracellular Ca 2+ concentration has been observed in many cells.…”

“…Hypoxia could activate the cytokine storm and inflammatory pathways and affect the fate of immune cells and functions. 1 Recently, it has been reported that the severity and death of COVID-19 patients is due to the hyperinflammation and activation of cytokine signaling. 5 Therefore, understanding these molecular mechanisms would be highly useful in prescribing or designing therapeutic approaches for the treatment of COVID-19 during the present global pandemic situation.…”

“…HIF-1 is the transcriptional activator of several genes concerning cellular adaption in the hypoxic state. 1 HIF-1α can increase the expression of glycolytic genes through binding hypoxia-responsive elements of glycolytic promoter genes. 8 …”