Biological markers of oxidative stress: Applications to cardiovascular research and practice

Abstract

Oxidative stress is a common mediator in pathogenicity of established cardiovascular risk factors. Furthermore, it likely mediates effects of emerging, less well-defined variables that contribute to residual risk not explained by traditional factors. Functional oxidative modifications of cellular proteins, both reversible and irreversible, are a causal step in cellular dysfunction. Identifying markers of oxidative stress has been the focus of many researchers as they have the potential to act as an "integrator" of a multitude of processes that drive cardiovascular pathobiology. One of the major challenges is the accurate quantification of reactive oxygen species with very short half-life. Redox-sensitive proteins with important cellular functions are confined to signalling microdomains in cardiovascular cells and are not readily available for quantification. A popular approach is the measurement of stable by-products modified under conditions of oxidative stress that have entered the circulation. However, these may not accurately reflect redox stress at the cell/tissue level. Many of these modifications are "functionally silent". Functional significance of the oxidative modifications enhances their validity as a proposed biological marker of cardiovascular disease, and is the strength of the redox cysteine modifications such as glutathionylation. We review selected biomarkers of oxidative stress that show promise in cardiovascular medicine, as well as new methodologies for high-throughput measurement in research and clinical settings. Although associated with disease severity, further studies are required to examine the utility of the most promising oxidative biomarkers to predict prognosis or response to treatment.

Keywords: Biomarker; CVD, cardiovascular disease; Cardiovascular disease; GSH, glutathione (reduced); Glutathionylation; H2O2, hydrogen peroxide; HO2•, hydroperoxyl radical; HOCl, hypochlorous acid; IsoP, isoprostane; MDA, malondialdehyde; MPO, myeloperoxidase; NO2, nitrogen dioxide; O2•−, superoxide; ONOO−, peroxynitrite; OxLDL, Oxidized low-density lipoprotein; Oxidative stress; Prognosis; ROS, reactive oxygen species; TBARS, thiobarbituric acid reacting substance; •OH, hydroxyl radical.

Graphical abstract

Fig. 1

Formation pathways of selected biomarkers of oxidative stress. Biomarkers that have been shown to have prognostic significance in cardiovascular disease are marked with ⁎. GSH=glutathione (reduced), PUFA=polyunsaturated fatty acids, see text for other abbreviations.

Fig. 2

Schematic timeline of required steps in biomarker development, from discovery in the Laboratory to clinical application after validation in large scale clinical trials. Although many ROS biomarkers have reached clinical trials level, only few are regularly applied to patients in clinical practice.

Fig. 3

Schematic illustration illustrating the functional effect of glutathionylation of key cardiovascular proteins eNOS [58], SERCA [13], and Na⁺–K⁺ pump [10,60].

Fig. 4

Schematic illustration of ROS as a common mediator of cardiovascular disease, making ROS-based biomarkers excellent “integrators” for total cardiovascular risk. The demonstrated effects of potent pharmacotherapies (e.g. ARB, angiotensin receptor blockers ; statins, HMG-CoA reductase inhibitors ; and β-blockers, β adrenergic receptor blockers [92]) on markers of oxidative stress suggest that biomarkers of ROS may be an early measure of the success of pharmacotherapy in a particular patient, and thus be a useful therapeutic guide in patients who are unable to tolerate a “cocktail” of agents.

Fig. 5

Schematic illustration of the potential application of ROS biomarker for early assessment of treatment efficacy, particularly useful for patients intolerant of combination therapies.