Beneficial Effects of Mineralocorticoid Receptor Pathway Blockade against Endothelial Inflammation Induced by SARS-CoV-2 Spike Protein.

Eva Jover,Lara Matilla,Patrick Rossignol,Pieter Muntendam,Amaya Fernández-Celis,Frédéric Jaisser,Natalia López-Andrés,Mattie Garaikoetxea

doi:10.3390/biomedicines9060639

Abstract

Background: Vascular endothelial cells activation and dysfunction mediate inflammation and abnormal coagulation in COVID-19 patients. Mineralocorticoid receptor (MR) signaling and its downstream target Galectin-3 (Gal-3) are known to mediate cardiovascular inflammation and might be involved in the pathogenesis of COVID-19 complications. Accordingly, we aimed to investigate the potential beneficial effects of MR antagonism and Gal-3 inhibition on the inflammatory response induced by SARS-CoV-2 Spike protein in human aortic endothelial cells (HAECs). Methods: HAECs were treated with recombinant SARS-COV2 Spike (S) protein. MR antagonists (namely spironolactone and eplerenone) or the Gal-3 inhibitor G3P-01 were supplemented before and after S protein challenge. HAECs supernatants were assessed by ELISA or Western blotting. Results: HAECs treated with recombinant S protein resulted in enhanced secretion of inflammatory molecules (interleukin-6, monocyte chemoattractant protein-1, interleukin-18, interleukin-27, and interferon-γ) as well as in the thrombosis marker plasminogen activator inhibitor (PAI)-1. This was prevented and reversed by both MR antagonists and G3P-01. Conclusions: These findings indicate that MR/Gal-3 pathway blockade could be a promising option to reduce endothelial inflammation in SARS-CoV-2 infection.

Highlights

The onset of severe COVID-19 presentation and subsequent complications encompasses respiratory symptoms, subsequently associated with a cytokine storm, which may combine disseminated intravascular coagulation and multiple organ failure
SARS-CoV2 binds to the host cell receptor Angiotensin-converting enzyme 2 (ACE2) through the
The expression of ACE2 and transmembrane protease serine 2 (TMPRSS2) was confirmed in human aortic endothelial cells (HAECs) (Figure 1)

Summary

Introduction

The onset of severe COVID-19 presentation and subsequent complications encompasses respiratory symptoms, subsequently associated with a cytokine storm, which may combine disseminated intravascular coagulation and multiple organ failure. The S protein is cleaved into the N-terminal S1 subunit and C terminal S2 subunit by the host transmembrane protease serine 2 (TMPRSS2) [1] Both ACE2 and TMPRSS2 are expressed by endothelial cells [2]. Results: HAECs treated with recombinant S protein resulted in enhanced secretion of inflammatory molecules (interleukin-6, monocyte chemoattractant protein-1, interleukin-18, interleukin-27, and interferon-γ) as well as in the thrombosis marker plasminogen activator inhibitor (PAI)-1. This was prevented and reversed by both MR antagonists and G3P-01. Conclusions: These findings indicate that MR/Gal-3 pathway blockade could be a promising option to reduce endothelial inflammation in SARS-CoV-2 infection

Objectives

Results

Conclusion