Disturbed flow enhances inflammatory signaling and atherogenesis by increasing thioredoxin-1 level in endothelial cell nuclei.

ABSTRACT:

Background

Oxidative stress occurs with disturbed blood flow, inflammation and cardiovascular disease (CVD), yet free-radical scavenging antioxidants have shown limited benefit in human CVD. Thioredoxin-1 (Trx1) is a thiol antioxidant protecting against non-radical oxidants by controlling protein thiol/disulfide status; Trx1 translocates from cytoplasm to cell nuclei due to stress signaling, facilitates DNA binding of transcription factors, e.g., NF-κB, and potentiates inflammatory signaling. Whether increased nuclear Trx1 contributes to proatherogenic signaling is unknown.

Methodology/principal findings

In vitro and in vivo atherogenic models were used to test for nuclear translocation of Trx1 and associated proinflammatory signaling. Disturbed flow by oscillatory shear stress stimulated Trx1 nuclear translocation in endothelial cells. Elevation of nuclear Trx1 in endothelial cells and transgenic (Tg) mice potentiated disturbed flow-stimulated proinflammatory signaling including NF-κB activation and increased expression of cell adhesion molecules and cytokines. Tg mice with increased nuclear Trx1 had increased carotid wall thickening due to disturbed flow but no significant differences in serum lipids or weight gain compared to wild type mice. Redox proteomics data of carotid arteries showed that disturbed flow stimulated protein thiol oxidation, and oxidation was higher in Tg mice than wild type mice.

Conclusions/significance

Translocation of Trx1 from cytoplasm to cell nuclei plays an important role in disturbed flow-stimulated proatherogenesis with greater cytoplasmic protein oxidation and an enhanced nuclear transcription factor activity. The results suggest that pharmacologic interventions to inhibit nuclear translocation of Trx1 may provide a new approach to prevent inflammatory diseases or progression.

SUBMITTER: Go YM 

PROVIDER: S-EPMC4180949 | biostudies-literature |

REPOSITORIES: biostudies-literature