COVID-19 promotes endothelial dysfunction and thrombogenicity: Role of pro-inflammatory cytokines/SGLT2 pro-oxidant pathway, 2023, Mroueh et al.

COVID-19 promotes endothelial dysfunction and thrombogenicity: Role of pro-inflammatory cytokines/SGLT2 pro-oxidant pathway
Ali Mroueh; Walaa Fakih; Adrien Carmona; Antonin Trimaille; Kensuke Matsushita; Benjamin Marchandot; Abdul Wahid Qureshi; Dal-Seong Gong; Cyril Auger; Laurent Sattler; Antje Reydel; Sébastien Hess; Walid Oulehri; Olivier Vollmer; Jean-Marc Lessinger; Nicolas Meyer; Michael-Paul Pieper; Laurence Jesel; Magnus Bäck; Valérie Schini-Kerth; Olivier Morel

Background
COVID-19 is associated with 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 hypothesizes that inflammation in COVID-19 patients contributes to endothelial dysfunction through redox sensitive SGLT2 overexpression and investigates the protective effect of SGLT2 inhibition by empagliflozin.

Methods
Human plasma samples were collected from acute, sub-acute and long COVID-19 patients (n=100), non-COVID-19 patients with cardiovascular risk factors (n=50), and healthy volunteers (n=25). Porcine coronary artery endothelial cells (ECs) were incubated with plasma (10%). Expression levels of proteins were determined using Western blot analyses and immunofluorescence staining, mRNA expression by RT-qPCR and the level of oxidative stress by dihydroethidium staining. Platelet adhesion and aggregation, and thrombin generation were determined.

Results
Increased plasma levels of IL-1β, IL-6, TNF-α, MCP-1 and sICAM-1 were observed in COVID-19 patients. Exposure of ECs to COVID-19 plasma with high cytokines levels induced redox-sensitive upregulation of SGLT2 expression via pro-inflammatory cytokines IL-1β, IL-6 and TNF-α which, in turn, fueled endothelial dysfunction, senescence, NF-κB activation, inflammation, platelet adhesion and aggregation, vWF secretion and thrombin generation. The stimulatory effect of COVID-19 plasma was blunted by neutralizing antibodies against pro-inflammatory cytokines, and by empagliflozin.

Conclusions
In COVID-19 patients, pro-inflammatory cytokines induced a redox-sensitive up-regulation 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.


Link | Paywall (Journal of Thrombosis and Haemostasis)