Peroxiredoxin 4, A Novel Circulating Biomarker for Oxidative Stress and the Risk of Incident Cardiovascular Disease and All‐Cause Mortality

Abstract

BackgroundOxidative stress has been suggested to play a key role in the development of cardiovascular disease (CVD). The aim of our study was to investigate the associations of serum peroxiredoxin 4 (Prx4), a hydrogen peroxide–degrading peroxidase, with incident CVD and all-cause mortality. We subsequently examined the incremental value of Prx4 for the risk prediction of CVD compared with the Framingham risk score (FRS).Methods and ResultsWe performed Cox regression analyses in 8141 participants without history of CVD (aged 28 to 75 years; women 52.6%) from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study in Groningen, The Netherlands. Serum Prx4 was measured by an immunoluminometric assay in baseline samples. Main outcomes were: (1) incident CVD events or CVD mortality and (2) all-cause mortality during a median follow-up of 10.5 years. In total, 708 participants (7.8%) developed CVD events or CVD mortality, and 517 participants (6.3%) died. Baseline serum Prx4 levels were significantly higher in participants with incident CVD events or CVD mortality and in those who died than in participants who remained free of outcomes (both P<0.001). In multivariable models with adjustment for Framingham risk factors, hazard ratios were 1.16 (95% CI 1.06 to 1.27, P<0.001) for incident CVD events or CVD mortality and 1.17 (95% CI 1.06 to 1.29, P=0.003) for all-cause mortality per doubling of Prx4 levels. After the addition of Prx4 to the FRS, the net reclassification improvement was 2.7% (P=0.01) using 10-year risk categories of CVD.ConclusionsElevated serum Prx4 levels are associated with a significantly higher risk of incident CVD events or CVD mortality and all-cause mortality after adjustment for clinical risk factors. The addition of Prx4 to the FRS marginally improved risk prediction of future CVD.

Regulation of Signal Transduction by Reactive Oxygen Species in the Cardiovascular System

“…60 Prx4 has been proposed to be a biomarker of oxidative stress based on evidence that patients with increased Prx4 have elevated CVD risk and mortality. 61 Prx6 exhibits both glutathione peroxidase and phospholipase A 2 activities, and is necessary for activation of Nox2 in endothelial cells and neutrophils. 62 …”

Increased peroxiredoxin 4 levels in patients with prediabetes compared to normal glucose tolerance subjects

“…[14][15][16] Some studies demonstrate that the increased levels of peroxiredoxin are linked to higher risk of cardiovascular diseases and increased cardiovascular mortality. 17 In patients with diabetes, peroxiredoxin levels are also correlated with cardiovascular complications and in combination with traditional risk factors have a predictive value for cardiovascular mortality risk. 18 There are, however, no data about its role in prediabetic conditions.…”

Roles of peroxiredoxins in cancer, neurodegenerative diseases and inflammatory diseases

“…Also, PRDX4 is secreted into an extracellular environment, therefore, its plasma concentration may be used as a molecular indicator of various cardiovascular disease and other disorders involving oxidative stress (Schulte, 2011). The increased serum PRDX4 concentration is considered as a good indicator of risk to cardiovascular disease because cardiovascular disease have higher level of oxidative stress and PRDX4 is overexpressed in these conditions (Abbasi et al, 2012). A study in a rat model of Wilson's disease has demonstrated that this disease has a lower level of PRDX4 expression as compared to normal (Ito et al, 2012).…”