The Protective Role of Glutaredoxin‐1 in Endothelial Barrier Regulation and Atherosclerosis

Abstract

Vascular oxidative stress is widely invoked as an important pathogenic mechanism for atherosclerosis (AS). Protein S‐glutathionylation (P‐SSG), the prevalent post‐translational oxidative modification, is emerging as a critical redox signaling mechanism in cardiovascular diseases. However, its role in AS is not clear yet. P‐SSG can be removed by glutaredoxin‐1 (Glrx), a thiol‐transferase which plays a pivotal role in redox signaling. This study is aimed to investigate the role of P‐SSG in high fat‐induced endothelial barrier dysfunction and AS through genetic manipulation of Glrx in human aortic endothelial cell (HAEC) and mice. Overexpression of Glrx attenuates high palmitate high glucose (HPHG)‐induced reversible oxidation of proteins and hyper‐permeability of HAEC monolayer to dextran. Consistently, high fat diet‐induced aortic vessel leakage indexed by dye extravasation is markedly decreased in Glrx transgenic mice when compared with WT mice. Overexpression of hGlrx‐1 in HAECs stimulates cortical actin filament formation under both basal and HPHG challenge conditions. Employing biotin‐switch assays, we showed that Glrx up‐regulation diminished HPHG‐induced oxidative modification of actin and the RhoGTPases, Rac‐1. More importantly, Glrx‐1 corrected HPHG‐induced Rac1 inactivation, a key mechanism of impaired endothelial barrier integrity. Oxidative stress‐induced endothelial barrier dysfunction is an initial step of AS, we thus assessed the high fat diet‐induced AS lesions by en face Oil red O staining in Glrx‐1 transgenic mice with ApoE deficiency background, and found that Glrx‐1 up‐regulation significantly attenuates AS lesion formation. These results suggest a causal role of P‐SSG in the pathogenesis of AS and that Glrx may have therapeutic potential for AS.