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Published on: August 20, 2019
COVID-19 promotes endothelial dysfunction and thrombogenicity: role of proinflammatory cytokines/SGLT2 prooxidant
Ali Mroueh1, Walaa Fakih1, Adrien Carmona2
1INSERM (French National Institute of Health and Medical Research), UMR 1260, Regenerative Nanomedicine, FMTS, Strasbourg, France.
Insights
COVID-19 increases cardiovascular risk by causing endothelial dysfunction via SGLT2 overexpression. Empagliflozin, an SGLT2 inhibitor, shows promise in restoring vascular health in COVID-19 patients.
Area of Science:
- Cardiovascular Medicine
- Molecular Biology
- Immunology
Background:
- COVID-19 is linked to heightened cardiovascular complications.
- Cytokines play a role in endothelial damage, but mechanisms remain unclear.
Purpose of the Study:
- To investigate if COVID-19 inflammation causes endothelial dysfunction via SGLT2 overexpression.
- To assess the protective effect of empagliflozin (SGLT2 inhibitor) against this dysfunction.
Main Methods:
- Analyzed plasma from COVID-19 patients, non-COVID-19 individuals, and healthy controls.
- Exposed endothelial cells (ECs) to plasma and measured SGLT2 expression, oxidative stress, and platelet activation.
- Utilized Western blot, immunofluorescence, qPCR, and dihydroethidium staining.
Main Results:
- COVID-19 patients showed elevated proinflammatory cytokines (IL-1β, IL-6, TNF-α).
- COVID-19 plasma induced SGLT2 upregulation in ECs, leading to dysfunction, senescence, and increased platelet activity.
- Empagliflozin and cytokine-neutralizing antibodies reduced these effects.
Conclusions:
- Proinflammatory cytokines in COVID-19 upregulate SGLT2, causing endothelial injury and thrombosis.
- SGLT2 inhibition with empagliflozin is a potential therapeutic strategy for vascular homeostasis in COVID-19.
Background:
COVID-19 is associated with an increased risk of cardiovascular complications. Although cytokines have a predominant role in endothelium damage, the precise molecular mechanisms are far from being elucidated.
Objectives:
The present study hypothesized that inflammation in patients with COVID-19 contributes to endothelial dysfunction through redox-sensitive SGLT2 overexpression and investigated the protective effect of SGLT2 inhibition by empagliflozin.
Methods:
Human plasma samples were collected from patients with acute, subacute, and long COVID-19 (n = 100), patients with non-COVID-19 and cardiovascular risk factors (n = 50), and healthy volunteers (n = 25). Porcine coronary artery endothelial cells (ECs) were incubated with plasma (10%). Protein expression levels were determined using Western blot analyses and immunofluorescence staining, mRNA expression by quantitative reverse transcription-polymerase chain reaction, and the level of oxidative stress by dihydroethidium staining. Platelet adhesion, aggregation, and thrombin generation were determined.
Results:
Increased plasma levels of interleukin (IL)-1β, IL-6, tumor necrosis factor-α, monocyte chemoattractant protein-1, and soluble intercellular adhesion molecule-1 were observed in patients with COVID-19. Exposure of ECs to COVID-19 plasma with high cytokines levels induced redox-sensitive upregulation of SGLT2 expression via proinflammatory cytokines IL-1β, IL-6, and tumor necrosis factor-α which, in turn, fueled endothelial dysfunction, senescence, NF-κB activation, inflammation, platelet adhesion and aggregation, von Willebrand factor secretion, and thrombin generation. The stimulatory effect of COVID-19 plasma was blunted by neutralizing antibodies against proinflammatory cytokines and empagliflozin.
Conclusion:
In patients with COVID-19, proinflammatory cytokines induced a redox-sensitive upregulation of SGLT2 expression in ECs, which in turn promoted endothelial injury, senescence, platelet adhesion, aggregation, and thrombin generation. SGLT2 inhibition with empagliflozin appeared as an attractive strategy to restore vascular homeostasis in COVID-19.
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