Endothelial dysfunction is a feature of thrombotic events reported in COVID-19 disease patients. However, the underlying molecular mechanisms of COVID-19-induced endothelial dysfunction are not clear.
Studies have shown that circulating levels of PAI-1, the coagulation cascade activator, are considerably higher in COVID-19 patients with severe respiratory illness compared to patients with bacterial-sepsis and acute respiratory distress syndrome (ARDS). Hence the increase in PAI-1 levels is recognized as an early marker of endothelial dysfunction in COVID-19 patients.
Examining the role played by protein degradation in the induction of PAI-1 by SARS-CoV-2-S1 protein
Researchers from Johns Hopkins University and the University of Science and Technology of China recently reported that recombinant SARS-CoV-2 spike glycoprotein stimulates the PAI-1 production by Human Pulmonary Microvascular Endothelial Cell (HPMEC). Their objective was to examine the role played by protein degradation in the induction of PAI-1 by this SARS-CoV-2-S1. They found that bortezomib, the proteasomal degradation inhibitor, impeded changes in PAI-1 induced by SARS-CoV-2-S1.
The data from the study, reported in the American Journal of Respiratory Cell and Molecular Biology, further showed that bortezomib upregulated KLF2, which is a shear-stress-regulated transcription factor that suppresses the expression of PAI-1.
Studies have shown that age and comorbidities such as metabolic disorders are major risk factors contributing to morbidity and mortality in COVID-19 patients. Hence, the authors examined the role of a metalloprotease ZMPSTE24 in the induction of PAI-1 in HPMEC by SARS-CoV-2-S1. ZMPSTE24 plays a role in host defense against RNA viruses, and it is decreased in the elderly and patients with metabolic syndrome.
Decrease in ZMPSTE24 make older COVID-19 patients with metabolic comorbidities more vulnerable to vascular endothelial injury
SARS-CoV-2 is believed to enter cells via the angiotensin-converting enzyme 2 (ACE2) receptor in the host cell. Recombinant SARS-CoV-2-S1 highly reduced expression of ACE2 in HeLa cells transfected with ACE2 cDNA. This has also been shown for other coronaviruses, such as SARS-CoV-1, which use the ACE2 receptor to enter the host cell.
Since ACE2 has been shown to protect against acute lung injury in several acute respiratory distress syndromes, its reduction could explain the compromised lung function seen in COVID-19 patients.
ACE2 protects the lungs by degrading angiotensin II (AngII) to angiotensin. AngII drives many adverse effects such as endothelial dysfunction, increased coagulation, inflammation, hypertension, oxidative stress, fibrosis, lung injury, and pulmonary hypertension.
Downregulation of ACE2 by the SARS-CoV-2-S1 protein offers evidence that this protein causes endothelial injury in the lungs of COVID-19 patients.
“The reduction in ACE2 could explain the compromised lung function of COVID-19 patients, as ACE2 has been reported to protect against acute lung injury in several models of acute respiratory distress syndrome.”
The findings of this study revealed that overexpression of ZMPSTE24 inhibited the PAI-1 production in spike protein-exposed HPMEC. They also found that membrane expression of the host receptor ACE2 was reduced by ZMPSTE24-mediated incision and shedding of the ACE2 ectodomain. This leads to the accumulation of ACE2 decoy fragments that may bind to the virus.
Overall, the data from this study indicate that decline in ZMPSTE24 with age and metabolic comorbidities may make COVID-19 patients more vulnerable to vascular endothelial injury by SARS-CoV-2 viruses. Also, the enhanced production of endothelial PAI-1 may have a role in prothrombotic events in patients with COVID-19.
Bortezomib may be repurposed to treat complications from endothelial dysfunction in COVID-19 patients
These findings offer new insights into the mechanisms of SARS-CoV-2 infection in the lung tissue. The pathogenesis of severe lung injury and respiratory dysfunction in COVID-19 patients shows a quantifiable means for assessing vulnerability to severe disease in key target populations.
The results also imply that bortezomib, currently used in multiple myeloma treatment, may be repurposed to treat complications from endothelial dysfunction and intravascular coagulation and speed up recovery from SARS-CoV-2 and other similar infections.
Studies have also shown that pharmacological inhibitors of PAI-1, including PAI-039 and MDI-2268, can inhibit atherosclerosis in mice with metabolic syndrome and obesity. More studies are needed in the future to determine if PAI-1 inhibitors can help treat thromboembolism and mortality in patients with COVID-19.
“The pathogenesis of severe acute lung injury and respiratory failure with COVID-19 suggests a quantifiable means for assaying vulnerability to these severe manifestations in key target subpopulations.”