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  • ZMPSTE24 Regulates SARS-CoV-2 Spike Protein-enhanced Expression of Endothelial PAI-1 #MMPMID34003736
  • Han M; Pandey D
  • Am J Respir Cell Mol Biol 2021[Sep]; 65 (3): 300-308 PMID34003736show ga
  • Endothelial dysfunction is implicated in the thrombotic events reported in patients with coronavirus disease (COVID-19), but the underlying molecular mechanisms are unknown. Circulating levels of the coagulation cascade activator PAI-1 are substantially higher in patients with COVID-19 with severe respiratory dysfunction than in patients with bacterial sepsis and acute respiratory distress syndrome. Indeed, the elevation of PAI-1 is recognized as an early marker of endothelial dysfunction. Here, we report that the rSARS-CoV-2-S1 (recombinant severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] viral envelope spike) glycoprotein stimulated robust production of PAI-1 by human pulmonary microvascular endothelial cells (HPMECs). We examined the role of protein degradation in this SARS-CoV-2-S1 induction of PAI-1 and found that the proteasomal degradation inhibitor bortezomib inhibited SARS-CoV-2-S1-mediated changes in PAI-1. Our data further show that bortezomib upregulated KLF2, a shear-stress-regulated transcription factor that suppresses PAI-1 expression. Aging and metabolic disorders are known to increase mortality and morbidity in patients with COVID-19. We therefore examined the role of ZMPSTE24 (zinc metallopeptidase STE24), a metalloprotease with a demonstrated role in host defense against RNA viruses that is decreased in older individuals and in metabolic syndrome, in the induction of PAI-1 in HPMECs by SARS-CoV-2-S1. Indeed, overexpression of ZMPSTE24 blunted enhancement of PAI-1 production in spike protein-exposed HPMECs. In addition, we found that membrane expression of the SARS-CoV-2 entry receptor ACE2 was reduced by ZMPSTE24-mediated cleavage and shedding of the ACE2 ectodomain, leading to accumulation of ACE2 decoy fragments that may bind SARS-CoV-2. These data indicate that decreases in ZMPSTE24 with age and comorbidities may increase vulnerability to vascular endothelial injury by SARS-CoV-2 viruses and that enhanced production of endothelial PAI-1 might play role in prothrombotic events in patients with COVID-19.
  • |Aging[MESH]
  • |COVID-19/metabolism/*virology[MESH]
  • |Cells, Cultured[MESH]
  • |Endothelial Cells/metabolism/*pathology/virology[MESH]
  • |Humans[MESH]
  • |Membrane Proteins/genetics/*metabolism[MESH]
  • |Metalloendopeptidases/genetics/*metabolism[MESH]
  • |Plasminogen Activator Inhibitor 1/genetics/*metabolism[MESH]
  • |Proteolysis[MESH]
  • |Pulmonary Artery/metabolism/*pathology/virology[MESH]
  • |SARS-CoV-2/*isolation & purification[MESH]
  • |Spike Glycoprotein, Coronavirus/genetics/*metabolism[MESH]

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  • suck abstract from ncbi

    300 3.65 2021