COVID-19 promotes endothelial dysfunction and thrombogenicity: Role of pro-inflammatory cytokines/SGLT2 pro-oxidant pathway

[SWAlexander]

Abstract​

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.
https://pubmed.ncbi.nlm.nih.gov/37797691/

Short explanation for: SGLT2 inhibition with empagliflozin. https://swaresearch.blogspot.com/2023/10/endothelium-inflammation-thrombosis.html

 

[wastwater]

I’m wondering about this for my diabetes

Metabolic basis of solute carrier transporters in treatment of type 2 diabetes mellitus​

https://www.sciencedirect.com/science/article/pii/S221138352300357X

Slc13a3 for myself probably

 

[wastwater]

https://www.mcknights.com/news/sglt2-inhibitors-reduce-dementia-parkinsons-disease-risk-study/

SGLT2 inhibitors reduce dementia, Parkinson’s disease risk: study​

 

[sb4]

I'm also now interested in sglt2 inhibitors.

They improve insulin resistance (which I suspect I have), reduce inflammation, improve cardiac disease, and chronic kidney disease.

I wonder how much of these improvements are downstream of improving insulin resistance? I know one study that showed benefits to cardiovascular disease in both diabetics and non diabetics.

 

[wastwater]

Does it tie in with the calcium/sodium channels work by Griffith university,another to trial for mecfs long covid maybe.
I wonder if I should swap the metformin for sglt2 and would it do anything different

 

[sb4]

Another interesting aspect for me is that I am an unsual POTS patient in that I have an aversion to salt and don't really drink much / get that thirsty. So inhibiting sglt2 cause the kidney to excrete more salt and water as well as glucose (for my suspected insulin resistance).

On top of that it should improve overall blood flow and inflammation via preventing SGLT2 from causing senescence, NF-kB activation, inflammation, platelet adhesion, von Willebrand factor secretion, and thrombin generation.

Since SGLT2 is activated by IL-1b, IL-6, TNFa, then its probable that SGLT2 is getting "over" expressed in ME / POTS patients.