AI Article Synopsis
- PAI-1 is associated with blood clotting issues and endothelial dysfunction in severe COVID-19, and certain genetic variations can affect its expression.
- Clinical studies on COVID-19 patients found that while comorbidities didn’t correlate with specific genotypes, the 4G/5G polymorphism showed differences in fibrinolytic factors and IL-1β levels.
- The 4G4G genotype was linked to high PAI-1 levels and suppressed fibrinolysis, while inflammation-related endothelial dysfunction was a risk for those with the 5G5G genotype.
Article Abstract
Introduction: Plasminogen activator inhibitor-1 (PAI-1) is linked to thrombosis and endothelial dysfunction in severe COVID-19. The +43 G>A PAI-1 and 4G/5G promoter polymorphism can influence PAI-1 expression. The 4G5G PAI-1 promoter gene polymorphism constitutes the 4G4G, 4G5G, and 5G5G genotypes. However, the impact of PAI-1 polymorphisms on disease severity or endothelial dysfunction remains unclear.
Methods: Clinical data, sera, and peripheral blood mononuclear cells (PBMCs) of COVID-19 patients were studied.
Results: Comorbidities and clinical biomarkers did not correlate with genotypes in either polymorphism. However, differences between fibrinolytic factors and interleukin-1β (IL-1β) were identified in genotypes of the 4G/5G but not the 43 G>A PAI polymorphism. Patients with the 4G4G genotype of the 4G/5G polymorphism showed high circulating PAI-1, mainly complexed with plasminogen activators, and low IL-1β and plasmin levels, indicating suppressed fibrinolysis. NFκB was upregulated in PBMCs of COVID-19 patients with the 4G4G genotype.
Discussion: Mechanistically, IL-1β enhanced PAI-1 expression in 4G4G endothelial cells, preventing the generation of plasmin and cleavage products like angiostatin, soluble uPAR, and VCAM1. We identified inflammation-induced endothelial dysfunction coupled with fibrinolytic system overactivation as a risk factor for patients with the 5G5G genotype.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11392769 | PMC |
| http://dx.doi.org/10.3389/fimmu.2024.1445294 | DOI Listing |
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