Hypoxia inducible factor-1 protects against COVID-19: A hypothesis.

The SARS-CoV-2 virus, the pathogen causing COVID 19, has been accepted as a pandemic by the World Health Organization. The most dreadful complication COVID 19 is hypoxemia due to respiratory failure. The mechanisms of lung damage and hypoxemia in COVID 19 include ventilation/perfusion mismatch, loss of hypoxic vasoconstriction and increased coagulopathy [1], [2], [3].

The SARS-CoV-2 virus binds and infects the cells via utilizing angiotensin converting enzyme 2 (ACE-2) as a receptor, which is found in lungs, kidneys, heart and arteries [4]. There are two types of ACE (ACE-1 and ACE-2) acting oppositely in pulmonary endothelium; ACE-2 functions as a vasodepressor whereas ACE-1 functions as a vasoconstrictor [5]. Under physiological conditions, there is a dynamic equilibrium between ACE-1 and ACE-2. However, in conditions of hypoxemia like COVID-19 infection, ACE-1 is upregulated by the hypoxia-inducible factor-1 (HIF-1); meanwhile the expression of ACE-2 is markedly decreased [6]. It has been suggested that increased levels of ACE-2 was positively associated with COVID-19 infection [7]. Thus, both hypoxemia and related ACE-2 upregulation may worsen clinical outcomes in COVID-19. Indeed, in a recent study, COVID-19 was less frequent in high altitudes (+2500 m above sea-level) due to physiological acclimatization to hypoxia, including potential depression of ACE-2, the main target of virus in pulmonary epithelia [5].

By the light of aforementioned data, we suggest that HIF-1 stabilization by HIF-1 stabilizers, a novel class of drugs to treat anemia, may dampen both hypoxia and adverse outcomes in COVID-19 infection by a variety of mechanisms. Firstly, during COVID-19 infection, there may be upregulation of HIF-1 due to hypoxia, which in turn downregulates ACE-2 levels, and thus may ameliorate COVID-19 infection. Secondly, HIF-1 stabilizers may be protective via their action on ferritin. In severe COVID-19 infection, serum ferritin levels are increased and may be utilized for risk stratification [8], [9]. In chronic inflammatory conditions, functional iron deficiency ensues, which is characterized by the inability to sufficiently mobilize iron from storage sites despite adequate iron stores, along with low transferrin saturation and normal to high serum ferritin levels, mostly due to elevated hepcidin levels [10]. Indeed, HIF-1 stabilizers downregulates hepcidin and ferritin levels and increases iron utilization and serum hemoglobin levels [11].

By the light of these findings, we suggest that HIF-1 stabilization may improve outcomes in COVID-19 infection by decreasing ferritin, ACE-2 levels and hypoxia.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.