A new diagnostic marker for cardiovascular diseases

In a recent article published in Circulation1, the team of Mustapha Rouis2 at the Institute of Biology Paris-Seine has identified the thioredoxin-80 (TRX-80) as a new marker for inflammatory and cardiovascular diseases (CVD). The team showed that the concentration of this protein in the blood increased with age. Of note, TRX-80 exerts pro-oxidant and pro-inflammatory effects and enhances atherosclerosis. Researchers have uncovered the molecular mechanisms that lead to the increase of this protein. Hence, the plasma level of TRX-80 could be used as a marker to evaluate the risk of age-related cardiovascular diseases.

The thioredoxin system, including thioredoxin-1 (TRX-1) and its cleaved form, TRX-80, is an essential system to maintain the oxidative balance in the body. TRX-1, a 12 kDa ubiquitous protein, plays an anti-inflammatory, anti-oxidant and anti-apoptotic role. In this study, researchers showed that the plasma level of TRX-1 decreased with age, due to an enzymatic cleavage that transforms this protein into a truncated form, TRX-80. In contrast to TRX-1, TRX-80 exerts pro-oxidant, pro-inflammatory, angiogenic and carcinogenic effects. TRX-80 also activates the inflammasome NLRP3, leading to the maturation of two pro-inflammatory and pro-athérogenic cytokines, IL-1b and IL-18. In addition, TRX-80 oriented macrophages to a pro-inflammatory M1-phenotype which accumulate within atheromatous plaques. This has been demonstrated on transgenic mice specifically overexpressing TRX-80 in macrophages. This accumulation of M1-macrophages in atheromatous plaques makes the later instable, fostering cardiovascular accidents.

This study explains, at least in part, why CVD and probably other inflammatory diseases such as diabetes, cancer, and arthritis increase with age. This work identifies TRX-80 as a new diagnostic marker for inflammatory and CVD.

Caption: TRX-1, a 12 kDa protein, is located in the cytoplasm. It protects cells, directly or indirectly, against oxidative damages, inflammation and apoptosis. Nevertheless, the plasma levels of TRX-1 decrease with age, while the plasma levels of TRX-80 increase. This is due to the increase of both expression and activity of 2 alpha-secretases (ADAM-10 and ADAM-17). TRX-80, unlike its native form, is pro-inflammatory, pro-atherogenic and pro-carcinogenic factor. The mechanisms involved in the regulation of the expression of these two alpha secretases are not yet fully understood.

1. Human Plasma Thioredoxin-80 Increases with Age and in apoE-/- Mice Induces Inflammation, Angiogenesis and Atherosclerosis ; Couchie D. et al, Circulation, 2017, May 4.

2. Team Integrative Cellular Ageing and Inflammation (UMR UPMC/CNRS 8256-IBPS, INSERM U1164).