Targeting Endogenous Antioxidants to Prevent Cardiovascular Diseases

O xidative stress has long been associated with a wide range of cardiovascular risk factors and likely contributes to the progression of cardiovascular diseases in animal models and in humans. Numerous lines of evidence indicate that pathways of oxidative and nitrative stress can contribute to cardiovascular disease via multiple mechanisms, such as through formation of atherogenic lipoproteins, initiation of lipid oxidation, and propagation of damage to endothelial cells and myocytes. Nevertheless, quantifying the degree of oxidative stress has posed major challenges because many of these processes occur intracellularly and involve complicated issues with stability and variability in biospecimens. Hence, the identification of biomarkers of oxidative stress has focused on detecting systemic stable oxidized products (eg, oxidized low-density lipoprotein, F2-isoprostanes) or identifying the presence of mediators of oxidative stress pathways (eg, oxidation of nitric oxide by myeloperoxidase and ceruloplasmin). In addition, quantifying the activities of endogenous antioxidant proteins such as high-density lipoprotein–associated paraoxonase-1 activities or glutathione may reflect underlying oxidative imbalance. Indeed, large prospective cohorts have identified individuals with abnormal levels of several of the aforementioned biomarkers to be at greater risk for future cardiovascular risks. Recently, a family of proteins called “peroxiredoxins” was described in various organisms. Peroxiredoxins are ubiquitously synthesized to reduce hydrogen peroxide and alkyl hydroperoxides to water and alcohol with the use of reducing equivalents derived from thiol-containing donor molecules. Peroxiredoxins has also been postulated to play a regulatory role in the activation of the transcription factor nuclear factorjB, and prevent the production of reactive oxygen species induced by epidermal growth factor or p53. Although the majority of peroxiredoxin proteins are intracellularly localized, peroxiredoxin-IV (Prx4, encoded by the gene) is the only known secretory form located in the extracellular space. Hence, the ability to detect circulating levels of Prx4 holds promise in quantifying oxidative stress for risk stratification. Evidence for peroxiredoxins in the development of cardiovascular diseases is emerging. In particular, the transgenic mouse model of human PRDX4 demonstrated protection of pancreatic beta cells against streptozotocin-induced injury as well as prevention of atherosclerosis formation in apolipoprotein E–null mice via suppression of oxidative stress and inflammatory signaling. These findings have provided promise that circulating Prx4 may have direct capabilities in cardiovascular protection, particularly in inflammatory disease states. In the October issue of JAHA, Abbasi and colleagues measured serum levels of Prx4 in the large Prevention of Renal and Vascular End-stage Disease study that included middle-aged subjects with microalbuminuria. They observed increased levels of Prx4 being associated with risk factors for cardiovascular diseases as well as incident development of cardiovascular events, even though the overall range of Prx4 levels was relatively low in this primary prevention cohort. It appears that Prx4 has a complex relationship with incident cardiovascular risk, whereby both very low and very high levels portend poorer outcomes. This is in direct contrast with other known endogenous antioxidants such as paraoxonase-1, whereby detection of low activity levels portends poorer outcomes. The authors hypothesized that low levels demonstrated insufficient antioxidant responses and high levels are suggestive of compensatory response toward heightened oxidative stress. In other words, Prx4 may better reflect underlying antioxidant response rather than underlying oxidative vulnerability; hence, these findings may hint that it is less likely for Prx4 (or the lack of) to function as a direct mediator of oxidative stress. The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Center for Cardiovascular Diagnostics and Prevention, Department of Cellular and Molecular Medicine, Lerner Research Institute, and Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH. Correspondence to: W. H. Wilson Tang, MD, 9500 Euclid Avenue, Desk J3-4, Cleveland, OH 44195. E-mail: [email protected] J Am Heart Assoc. 2012;1:e005215 doi: 10.1161/JAHA.112.005215. a 2012 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley-Blackwell. This is an Open Access article under the terms of the Creative Commons Attribution Noncommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.