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Peroxiredoxin 4: a multifunctional biomarker worthy of further exploration
© Schulte; licensee BioMed Central Ltd. 2011
Received: 26 August 2011
Accepted: 23 December 2011
Published: 23 December 2011
Currently, there is much interest in identifying clinically relevant biomarkers, as they have the potential to be high utility non-invasive tools for early diagnosis and reliable patient monitoring in numerous conditions. Since its discovery almost 15 years ago, research on the ubiquitous antioxidant enzyme peroxiredoxin 4 (Prx4) has culminated in the recognition that Prx4 levels are different in blood drawn from the healthy general population and patients with acute or chronic diseases. In this commentary, the most striking research data from different in vitro approaches, animal models and human observational studies are discussed collectively, highlighting the clinical importance of Prx4 as a multifunctional staging and prognosis biomarker. In this context, the oxidative state of patients may be reflected by intra- and extracellular Prx4 levels, redox state, oligomerization and nitro-oxidative modifications of the enzyme. A consolidated model of the potential role and origin of circulating Prx4 is presented to stimulate further investigations in light of the current biomarker situation.
Physiologically important processes such as redox signaling and host defense depend on balanced amounts of reactive oxygen species (ROS), including free radicals and stable oxidizing molecules, for example, hydrogen peroxide (H2O2). In conditions of oxidative stress, increased ROS levels overwhelm antioxidant protection mechanisms, resulting in the development and progression of various diseases .
Peroxiredoxin 4 (Prx4; synonyms: AOE372, TRANK) is a ubiquitously expressed member of the peroxiredoxin family that is localized in the endoplasmic reticulum (ER) and extracellular space [2, 3], with highest expression in the pancreas, liver and heart, and lowest expression in blood leukocytes and the brain [2, 4]. The enzyme diminishes oxidative stress by reducing hydrogen peroxide to water in a thiol-dependent catalytic cycle  and has been linked to the regulation of the key pro-inflammatory transcription factor, nuclear factor kappa B (NF-κB) [2, 4, 6]. In addition, redox-dependent and reversible conversion of homologous Prx1-4 from disulfide-linked homodimers to higher-order multimers and back provides a versatile mechanism to switch between peroxidase and chaperone activity, enabling interaction with binding partners including stress-responsive kinases, membrane proteins and immune-modulators, fine-tuning of H2O2 signaling  and, as published most recently, circadian clock oscillations . Disturbances in the aforementioned fundamental processes clearly result in numerous pathological conditions that could potentially be reflected by the measurement of involved Prx.
Among the six Prx isoforms in mammals, Prx4 emerges as the most attractive, easily accessible biomarker candidate as it was initially designated as a secretable peroxidase [2, 9], has recently been identified in the circulation of healthy and diseased individuals [10, 11] and, finally, has been linked to morbidity and mortality in patients with sepsis in the intensive care unit and patients with non-specific complaints in the emergency department [12, 13]. In addition, several studies have shown that the expression or oxidation state of Prx4 changes under pathological conditions such as cancer [14–20], diabetes [21–23] and infection [4, 6, 24–27].
Fast evolving genomic and proteomic studies constantly provide many new biomarker candidates, unavoidably lacking a differentiated evaluation of single candidates and possibly misdirecting promising fields of application. Hence, this commentary intends to discuss the available data on Prx4 at an early stage, focusing on the relevant clinical evidence that indicates strong biomarker potential in a number of conditions in critical care and the emergency room.
Clinical significance of Prx4 detection
Prx4 should be of special interest to clinicians as it may represent a new marker candidate that could be highly valuable in predicting the prognosis of an adverse outcome to risk stratify patients and to monitor therapy. Indeed, serum and expression levels, as well as post-translational modifications, of the enzyme have been linked to a number of different diseases, ranging from primary care to advanced critical care topics (see Additional file 1). The biomarker performance of Prx4 in these patients is truly encouraging, given the high heterogeneity and potential confounders, such as co-morbidities and medication. Indeed, Prx4 expression in the mouse liver was responsive to different drugs, including the analgesic paracetamol and the chemotherapeutic etoposide phosphate . Altogether, Prx4 is assumed to be important in many single settings, which is very promising, but requires further validation. The results found by Chang and colleagues , for instance, are methodologically questionable because they are based on an immunoassay that worked with diluted patient plasma directly coated to the solid phase, which strongly limits specific antibody binding. Moreover, findings from different cancer studies are in part contradictory, concluding either good [16, 18] or bad prognosis [14, 19] from increased Prx4 expression in tumor tissue. Specifically, sepsis , cancer  and cardiovascular disease  are candidate diseases where Prx4 measurement may be of particular use as they share redox and inflammatory dysregulation and frequently lack valid severity and risk assessment by non-invasive biomarkers.
Perspectives for Prx4 testing methods
An improved understanding of the redox regulation, structural assembly and activity of Prx4 would provide a better insight into analyzing Prx4 as a biomarker in tissue or serum. Conoidin A, a specific Prx activity inhibitor, is currently under evaluation . Tavender and Bulleid found Prx4 oxidation to be indicative of the degree of oxidative stress in the ER . Atherosclerotic plaque development (Full et al., unpublished data), viral infection of A549 lung adenocarcinoma epithelial cells  and stimulation of human umbilical vein endothelial cells (HUVEC) with H2O2 and hydroperoxides  resulted in oxidation and a shifted isoelectric point of Prx4, respectively. Moreover, selective changes for either a putative 31-kDa precursor or 27-kDa secretable Prx4 have been reported in lung cancer  and spermatogenesis disorders [35, 36]. Consequently, detection of Prx4 hyperoxidation and oligomerization [3, 25, 37, 38] could be a meaningful, albeit challenging, measure of thiol-redox imbalances and should be integrated into Prx4 analysis. Existing expression data, however, require careful interpretation in light of a newly discovered 29.5-kDa splice variant of Prx4  that cannot be recognized by the antibodies used in the immunoassay that has been developed for the detection of Prx4 dimers and oligomers in serum .
Origin and drivers of circulating Prx4
Consequences of Prx4 modification
It seems reasonable by now to expand basic clinical research from exclusive expression studies to mechanisms of Prx4 release, oligomerization and oxidative modification in order to identify relevant biochemical interrelations and refine the actual biomarker value of Prx4. Present data indicate that Prx4, either intracellular or extracellular, has the potential to serve as a biomarker for both the early staging of disease severity and the prediction of the future disease course in different pathologies that involve dysregulation of the redox system, for example, as evident during inflammatory processes. Accordingly, it is recommended that promising results from recent studies be validated and clinical trials be performed in new indications to ultimately assess the overall use of Prx4 for risk stratification and therapy monitoring in comparison with existing standards.
The author is indebted to Dr Joachim Struck for reviewing the manuscript.
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