SARS-CoV-2 infecting endothelial cells, biochemical alterations, autopsy findings and outcomes in COVID-19, suggest role of hypoxia-inducible factor-1

Abstract

Researchers around the world have experienced the dual nature of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), ‘tragically lethal in some persons and surprisingly benign in others’. They have congregated to study novel coronavirus disease (COVID-19), a disease that mainly attacks the lungs, but also has mystifying effects on the heart, kidneys and brain. Researchers are also gathering information to determine what actually kills COVID-19 patients, whether respiratory disorder or coagulation disorder or multi organ failure. Various laboratory parameters like lactate, ferritin, hypoalbuminemia have been established as risk factor or associated with poor outcomes, but yet could not be substantiated with the scientific biochemical rationale. 
 SARS-CoV-2 affects the alveolar type II epithelial cells, that significantly disturbs its surfactant homeostasis, deprive Na,K-ATPase of ATP, thereby disturbing the alveolar lining fluid which then gradually decreases the alveolar gaseous exchange initiating intracellular hypoxic conditions. This activates AMP-activated kinase, which further inhibits Na,K-ATPase, that can progressively cause respiratory distress syndrome.
 The virus may infect endothelial cell (EC), which being low energetic, cannot withstand the huge energy requirement towards viral replication, and therefore glycolysis, the prime energy generating pathway, has to mandatorily be upregulated, which can be achieved by Hypoxia-inducible factor 1 (HIF-1). However, HIF-1 activates transcription of von Willebrand factor, plasminogen activator inhibitor-1, and suppresses the release of thrombomodulin, thereby setting off the coagulation cascade that leads to in-situ pulmonary thrombosis and micro clots.
 The proposed HIF-1 hypothesis can rationalize various features, clinical laboratory as well as autopsy findings such as respiratory distress syndrome, increased blood ferritin and lactate levels, endothelial invasion, in-situ pulmonary thrombosis and micro clots, and multiorgan failure in COVID -19
 Keywords: novel coronavirus, COVID-19, SARS-CoV-2, severe acute respiratory syndrome coronavirus 2, hypoxia-inducible factor-1

Neurological Manifestations of SARS-CoV-2 Infection: Protocol for a Sub-analysis of the COVID-19 Critical Care Consortium Observational Study

“…neurologic events. Indeed, COVID-19 patients are at high risk of hypoxia, hypotension, and microvascular abnormalities (13)(14)(15) which can promote neuroinflammation and excitotoxicity and increased permeability of the blood brain barrier (16). The risk is even more increased by the use of extracorporeal membrane oxygenation (ECMO) support that is a salvage option in COVID-19 critically ill patients with refractory hypoxemia (17).…”

In silico investigation of phenolic derivatives from Silybum marianum against SARS-CoV-2 proteins as a pharmacological drug repurposing strategies to mitigate the pandemic.

“…As silymarin is in the clinical trial pipeline and its less toxic properties is a unique characteristic which can ensure it as an effective drug molecule for different disease, we evaluated the efficacy of the molecule towards main protease, spike receptor binding domain and RNA binding domain of nucleocapsid phosphoprotein enzymes of SARS-CoV-2 [8]. The COVID-19 disease basically affects the endothelial lining of the lungs and the disease progression also relates to the physiological changes as in case of high-altitude hypoxia illness [9]. Hence, we want to check the possibility of Silibinin(a major constituent of silymarin) as an effective inhibitor.…”

An Evidence of Drug Repurposing for COVID-19 Pandemic Based on <i>In silico</i> Investigation from Phenolic Derivatives of Silybum Marianum Against SARS-Cov-2 Proteins

“…As silymarin is in the clinical trial pipeline and its less toxic properties is a unique characteristic that can ensure it as an effective drug molecule for a different disease, we evaluated the efficacy of the molecule towards main protease, spike receptor binding domain and RNA binding domain of nucleocapsid phosphoprotein enzymes of SARS-CoV-2 [8]. The COVID-19 disease affects the endothelial lining of the lungs and the disease progression also relates to physiological changes as in the case of high-altitude hypoxia illness [9]. Hence, we want to check the possibility of silibinin (a major constituent of silymarin) as an effective inhibitor.…”