Abstract 13989: Glutaredoxin-1: A Redox Regulator of Metalloproteases in Vascular Endothelial Cells

Abstract

Background: Endothelial dysfunction is a common mediator of aneurysmal remodeling regardless of etiology and the vascular bed that occur (e.g., genetic mutations, hypertension, aging, smoking, abdominal or thoracic artery or aortic root), but the underlying mechanisms remain unknown. This work aims to test the hypothesis that perturbing thiol redox signaling in endothelial cells triggers aberrant activation of matrix metalloproteinase-2 and -9, thereby precipitating aneurysmal remodeling. Methods and Results: In human aortic aneurysm (AA) samples from individuals with Marfan syndrome, levels of MMP-2/-9 were increased drastically that coincided with elevated oxidative stress markers: tyrosine nitrated proteins and lipid peroxidation product 4-hydroxynonenal . In mouse model of AA: fibrillin-1 mutant( Fbn1 mgR/mgR ) mice, reversible oxidation of cysteine residues—S-glutathionylation (PrS-SG) that mediate thiol redox signaling by modulating target proteins’ functions—were markedly elevated as an early redox event. Endothelial specific deletion of glutaredoxin-1(Grx1), a specific de-glutathionylation enzyme was found to massively increase gelatinase activity of MMP-2/-9 in whole aortas, and worsen vessel wall integrity. Using primary human aortic ECs, we showed that Grx1 can directly prevent pro-MMP-2/-9 from glutathionylation of their cysteine switch and consequent activation. Furthermore, the medium collected from HAECs that lack functional Grx1 stimulated MMP-2 activity in smooth muscle cells, thus setting up an amplifying mechanism of MMP activation. Conclusions: this study is the first to provide experiment evidence for a pathogenic role of dysregulated thiol redox signaling in vascular endothelial cells in aneurysmal remodeling.