Eva Jover1, Lara Matilla1, Mattie Garaikoetxea1, Amaya Fernández-Celis1, Pieter Muntendam2, Frédéric Jaisser3,4,5, Patrick Rossignol4,5, Natalia López-Andrés1. 1. Cardiovascular Translational Research, Navarrabiomed (Miguel Servet Foundation), Instituto de Investigación Sanitaria de Navarra (IdiSNA), Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), 31008 Pamplona, Spain. 2. G3 Pharmaceuticals, Burlington, MA 01803, USA. 3. Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, 75006 Paris, France. 4. Centre d'Investigations Cliniques-Plurithématique (INSERM CIC-PT 1433), UMR 1116, CHRU, Université de Lorraine, 54500 Vandoeuvre-Les-Nancy, France. 5. French-Clinical Research Infrastructure Network (F-CRIN) Cardiovascular and Renal Clinical Trialists (INI-CRCT), 54500 Nancy, France.
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.
BACKGROUND: Vascular endothelial cells activation and dysfunction mediate inflammation and abnormal coagulation in COVID-19patients. 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-2Spike protein in human aortic endothelial cells (HAECs). METHODS: HAECs were treated with recombinant SARS-COV2Spike (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.
Authors: Timothy F Spracklen; Simon C Mendelsohn; Claire Butters; Heidi Facey-Thomas; Raphaella Stander; Debbie Abrahams; Mzwandile Erasmus; Richard Baguma; Jonathan Day; Christiaan Scott; Liesl J Zühlke; George Kassiotis; Thomas J Scriba; Kate Webb Journal: Front Immunol Date: 2022-09-06 Impact factor: 8.786