Mineralocorticoid receptor-antagonism prevents COVID-19-dependent glycocalyx damage

Abstract

Proinflammatory cytokines target vascular endothelial cells during COVID-19 infections. In particular, the endothelial glycocalyx (eGC), a proteoglycan-rich layer on top of endothelial cells, was identified as a vulnerable, vasoprotective structure during infections. Thus, eGC damage can be seen as a hallmark in the development of endothelial dysfunction and inflammatory processes. Using sera derived from patients suffering from COVID-19, we could demonstrate that the eGC became progressively worse in relation to disease severity (mild vs severe course) and in correlation to IL-6 levels. This could be prevented by administering low doses of spironolactone, a well-known and highly specific aldosterone receptor antagonist. Our results confirm that SARS-CoV-2 infections cause eGC damage and endothelial dysfunction and we outline the underlying mechanisms and suggest potential therapeutic options.

Integrative Systems Immunology Analysis Reveals Elevated Anti-AGTR1 Levels with Accumulating COVID-19 Symptoms

“…Inflammation-induced degradation of the eGC, a critical component in preserving endothelial function, has been implicated in the pathogenesis of COVID-19-related endothelial dysfunction 46–48 . Utilizing an anti-AGTR1 monoclonal antibody (mAb) across various concentrations (10, 50, and 100 µg/mL), we observed concentration-dependent reductions in eGC height and increases in stiffness compared to isotype controls ( Figure 6a ).…”

Therapeutic strategies targeting the endothelial glycocalyx

“…There have also been several successful strategies aimed at restoring the glycocalyx to accelerate COVID-19 recovery. The mineralocorticoid receptor antagonist spironolactone has been shown to improve glycocalyx thickness in mild COVID-19 cases [40]. Another study tested whether glycocalyx degradation could be restored, cultured human primary pulmonary microvascular endothelial cells in the presence of both COVID patient sera and the heparin sulfate mimetic fucoidan.…”

“…Recent studies have shown a link between COVID-19 and endothelial glycocalyx damage, as patients with COVID-19 have impaired glycocalyx barrier function [39]. The level of glycocalyx damage may be dependent on COVID-19 severity, as in vitro findings indicate that blood derived from patients with mild symptoms reduced the glycocalyx by approximately 49%, whereas sera from patients with severe symptoms reduced the height of the glycocalyx by >60% [40]. COVID-19 severity is also related to the magnitude of elevation in blood concentrations of syndecan-1, heparinase, heparin sulfate, and hyaluronan [37,40,41 ▪▪ ,42,43,44 ▪ ,45].…”

“…The level of glycocalyx damage may be dependent on COVID-19 severity, as in vitro findings indicate that blood derived from patients with mild symptoms reduced the glycocalyx by approximately 49%, whereas sera from patients with severe symptoms reduced the height of the glycocalyx by >60% [40]. COVID-19 severity is also related to the magnitude of elevation in blood concentrations of syndecan-1, heparinase, heparin sulfate, and hyaluronan [37,40,41 ▪▪ ,42,43,44 ▪ ,45]. The loss of syndecan-1 from the endothelial glycocalyx leads to increased adhesion of leukocytes to endothelial cells, enhanced vascular permeability, and intravascular coagulation [39,40,46], which is a major concern as glycocalyx damage could increase the severity of inflammatory response to COVID-19, as well as the length of recovery.…”

“…COVID-19 severity is also related to the magnitude of elevation in blood concentrations of syndecan-1, heparinase, heparin sulfate, and hyaluronan [37,40,41 ▪▪ ,42,43,44 ▪ ,45]. The loss of syndecan-1 from the endothelial glycocalyx leads to increased adhesion of leukocytes to endothelial cells, enhanced vascular permeability, and intravascular coagulation [39,40,46], which is a major concern as glycocalyx damage could increase the severity of inflammatory response to COVID-19, as well as the length of recovery. Indeed, endothelial damage has been found to persist even months after infection (i.e., long COVID), with studies indicating residual glycocalyx damage and endothelial dysfunction four months after infection [46,47].…”