Abstract
Peroxiredoxin (Prx) refers to a family of thiol-dependent peroxidases that decompose hydrogen peroxide, lipid hydroperoxides, as well as peroxynitrite, and protect against oxidative and inflammatory stress. There are six mammalian Prx isozymes (Prx1–6), classified as typical 2-Cys, atypical 2-Cys, or 1-Cys Prxs based on the mechanism and the number of cysteine residues involved during catalysis. In addition to their well-established peroxide-scavenging activity, some Prxs also participate in the regulation of various cell signaling pathways. Extensive animal studies employing primarily gene knockout models provide substantial evidence supporting a critical protective role of Prxs in various disease processes involving oxidative and inflammatory stress. This review surveys recent research findings, published primarily in influential journals, on the involvement of various Prx isozymes in protecting against cardiovascular injury and related disorders, including diabetes, metabolic syndromes, and sepsis, whose pathophysiology all intimately involves oxidative stress and inflammation.
Similar content being viewed by others
Abbreviations
- ApoE:
-
Apolipoprotein E
- LPS:
-
Lipopolysaccharide
- PDGF:
-
Platelet-derived growth factor
- Prx:
-
Peroxiredoxin
- Trx:
-
Thioredoxin
References
Kim, K., Kim, I. H., Lee, K. Y., Rhee, S. G., & Stadtman, E. R. (1988). The isolation and purification of a specific "protector" protein which inhibits enzyme inactivation by a thiol/Fe(III)/O2 mixed-function oxidation system. Journal of Biological Chemistry, 263(10), 4704–4711.
Salzano, S., Checconi, P., Hanschmann, E. M., Lillig, C. H., Bowler, L. D., Chan, P., et al. (2014). Linkage of inflammation and oxidative stress via release of glutathionylated peroxiredoxin-2, which acts as a danger signal. Proceedings of the National Academy of Sciences of the United States of America, 111(33), 12157–12162. https://doi.org/10.1073/pnas.1401712111.
Bryk, R., Griffin, P., & Nathan, C. (2000). Peroxynitrite reductase activity of bacterial peroxiredoxins. Nature, 407(6801), 211–215. https://doi.org/10.1038/35025109.
Manta, B., Hugo, M., Ortiz, C., Ferrer-Sueta, G., Trujillo, M., & Denicola, A. (2009). The peroxidase and peroxynitrite reductase activity of human erythrocyte peroxiredoxin 2. Archives of Biochemistry and Biophysics, 484(2), 146–154. https://doi.org/10.1016/j.abb.2008.11.017.
De Armas, M. I., Esteves, R., Viera, N., Reyes, A. M., Mastrogiovanni, M., Alegria, T. G. P., et al. (2019). Rapid peroxynitrite reduction by human peroxiredoxin 3: Implications for the fate of oxidants in mitochondria. Free Radical Biology and Medicine, 130, 369–378. https://doi.org/10.1016/j.freeradbiomed.2018.10.451.
Chen, J. W., Dodia, C., Feinstein, S. I., Jain, M. K., & Fisher, A. B. (2000). 1-Cys peroxiredoxin, a bifunctional enzyme with glutathione peroxidase and phospholipase A2 activities. Journal of Biological Chemistry, 275(37), 28421–28427. https://doi.org/10.1074/jbc.M005073200.
Kisucka, J., Chauhan, A. K., Patten, I. S., Yesilaltay, A., Neumann, C., Van Etten, R. A., et al. (2008). Peroxiredoxin1 prevents excessive endothelial activation and early atherosclerosis. Circulation Research, 103(6), 598–605. https://doi.org/10.1161/CIRCRESAHA.108.174870.
Jeong, S. J., Kim, S., Park, J. G., Jung, I. H., Lee, M. N., Jeon, S., et al. (2018). Prdx1 (peroxiredoxin 1) deficiency reduces cholesterol efflux via impaired macrophage lipophagic flux. Autophagy, 14(1), 120–133. https://doi.org/10.1080/15548627.2017.1327942.
Stancill, J. S., Happ, J. T., Broniowska, K. A., Hogg, N., & Corbett, J. A. (2020). Peroxiredoxin 1 plays a primary role in protecting pancreatic ss-cells from hydrogen peroxide and peroxynitrite. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology. https://doi.org/10.1152/ajpregu.00011.2020.
Wang, Q. M., Cai, Y., Tian, D. R., Yang, H., Wei, Z. N., Wang, F., et al. (2010). Peroxiredoxin1: A potential obesity-related factor in the hypothalamus. Medical Science Monitor, 16(10), BR321–BR326.
Choi, M. H., Lee, I. K., Kim, G. W., Kim, B. U., Han, Y. H., Yu, D. Y., et al. (2005). Regulation of PDGF signalling and vascular remodelling by peroxiredoxin II. Nature, 435(7040), 347–353. https://doi.org/10.1038/nature03587.
Sundaresan, M., Yu, Z. X., Ferrans, V. J., Irani, K., & Finkel, T. (1995). Requirement for generation of H2O2 for platelet-derived growth factor signal transduction. Science, 270(5234), 296–299. https://doi.org/10.1126/science.270.5234.296.
He, C., Medley, S. C., Hu, T., Hinsdale, M. E., Lupu, F., Virmani, R., et al. (2015). PDGFRbeta signalling regulates local inflammation and synergizes with hypercholesterolaemia to promote atherosclerosis. Nature Communications, 6, 7770. https://doi.org/10.1038/ncomms8770.
Park, J. G., Yoo, J. Y., Jeong, S. J., Choi, J. H., Lee, M. R., Lee, M. N., et al. (2011). Peroxiredoxin 2 deficiency exacerbates atherosclerosis in apolipoprotein E-deficient mice. Circulation Research, 109(7), 739–749. https://doi.org/10.1161/CIRCRESAHA.111.245530.
Jang, J. Y., Wang, S. B., Min, J. H., Chae, Y. H., Baek, J. Y., Yu, D. Y., et al. (2015). Peroxiredoxin II is an antioxidant enzyme that negatively regulates collagen-stimulated platelet function. Journal of Biological Chemistry, 290(18), 11432–11442. https://doi.org/10.1074/jbc.M115.644260.
Federti, E., Matte, A., Ghigo, A., Andolfo, I., James, C., Siciliano, A., et al. (2017). Peroxiredoxin-2 plays a pivotal role as multimodal cytoprotector in the early phase of pulmonary hypertension. Free Radical Biology and Medicine, 112, 376–386. https://doi.org/10.1016/j.freeradbiomed.2017.08.004.
Kang, S. W., Chang, T. S., Lee, T. H., Kim, E. S., Yu, D. Y., & Rhee, S. G. (2004). Cytosolic peroxiredoxin attenuates the activation of Jnk and p38 but potentiates that of Erk in Hela cells stimulated with tumor necrosis factor-alpha. Journal of Biological Chemistry, 279(4), 2535–2543. https://doi.org/10.1074/jbc.M307698200.
Yang, C. S., Lee, D. S., Song, C. H., An, S. J., Li, S., Kim, J. M., et al. (2007). Roles of peroxiredoxin II in the regulation of proinflammatory responses to LPS and protection against endotoxin-induced lethal shock. Journal of Experimental Medicine, 204(3), 583–594. https://doi.org/10.1084/jem.20061849.
Matsushima, S., Ide, T., Yamato, M., Matsusaka, H., Hattori, F., Ikeuchi, M., et al. (2006). Overexpression of mitochondrial peroxiredoxin-3 prevents left ventricular remodeling and failure after myocardial infarction in mice. Circulation, 113(14), 1779–1786. https://doi.org/10.1161/CIRCULATIONAHA.105.582239.
Tsutsui, H., Kinugawa, S., & Matsushima, S. (2009). Mitochondrial oxidative stress and dysfunction in myocardial remodelling. Cardiovascular Research, 81(3), 449–456. https://doi.org/10.1093/cvr/cvn280.
Nickel, A. G., von Hardenberg, A., Hohl, M., Loffler, J. R., Kohlhaas, M., Becker, J., et al. (2015). Reversal of mitochondrial transhydrogenase causes oxidative stress in heart failure. Cell Metabolism, 22(3), 472–484. https://doi.org/10.1016/j.cmet.2015.07.008.
Dey, S., DeMazumder, D., Sidor, A., Foster, D. B., & O'Rourke, B. (2018). Mitochondrial ROS drive sudden cardiac death and chronic proteome remodeling in heart failure. Circulation Research, 123(3), 356–371. https://doi.org/10.1161/CIRCRESAHA.118.312708.
Chen, L., Na, R., Gu, M., Salmon, A. B., Liu, Y., Liang, H., et al. (2008). Reduction of mitochondrial H2O2 by overexpressing peroxiredoxin 3 improves glucose tolerance in mice. Aging Cell, 7(6), 866–878. https://doi.org/10.1111/j.1474-9726.2008.00432.x.
Arkat, S., Umbarkar, P., Singh, S., & Sitasawad, S. L. (2016). Mitochondrial peroxiredoxin-3 protects against hyperglycemia induced myocardial damage in diabetic cardiomyopathy. Free Radical Biology and Medicine, 97, 489–500. https://doi.org/10.1016/j.freeradbiomed.2016.06.019.
Huh, J. Y., Kim, Y., Jeong, J., Park, J., Kim, I., Huh, K. H., et al. (2012). Peroxiredoxin 3 is a key molecule regulating adipocyte oxidative stress, mitochondrial biogenesis, and adipokine expression. Antioxidants & Redox Signaling, 16(3), 229–243.
Li, L., Shoji, W., Takano, H., Nishimura, N., Aoki, Y., Takahashi, R., et al. (2007). Increased susceptibility of MER5 (peroxiredoxin III) knockout mice to LPS-induced oxidative stress. Biochemical and Biophysical Research Communications, 355(3), 715–721. https://doi.org/10.1016/j.bbrc.2007.02.022.
Guo, X., Yamada, S., Tanimoto, A., Ding, Y., Wang, K. Y., Shimajiri, S., et al. (2012). Overexpression of peroxiredoxin 4 attenuates atherosclerosis in apolipoprotein E knockout mice. Antioxidants & Redox Signaling, 17(10), 1362–1375. https://doi.org/10.1089/ars.2012.4549.
Ding, Y., Yamada, S., Wang, K. Y., Shimajiri, S., Guo, X., Tanimoto, A., et al. (2010). Overexpression of peroxiredoxin 4 protects against high-dose streptozotocin-induced diabetes by suppressing oxidative stress and cytokines in transgenic mice. Antioxidants & Redox Signaling, 13(10), 1477–1490. https://doi.org/10.1089/ars.2010.3137.
Nabeshima, A., Yamada, S., Guo, X., Tanimoto, A., Wang, K. Y., Shimajiri, S., et al. (2013). Peroxiredoxin 4 protects against nonalcoholic steatohepatitis and type 2 diabetes in a nongenetic mouse model. Antioxidants & Redox Signaling, 19(17), 1983–1998. https://doi.org/10.1089/ars.2012.4946.
Mehmeti, I., Lortz, S., Elsner, M., & Lenzen, S. (2014). Peroxiredoxin 4 improves insulin biosynthesis and glucose-induced insulin secretion in insulin-secreting INS-1E cells. Journal of Biological Chemistry, 289(39), 26904–26913. https://doi.org/10.1074/jbc.M114.568329.
Lipinski, S., Pfeuffer, S., Arnold, P., Treitz, C., Aden, K., Ebsen, H., et al. (2019). Prdx4 limits caspase-1 activation and restricts inflammasome-mediated signaling by extracellular vesicles. EMBO Journal, 38(20), e101266. https://doi.org/10.15252/embj.2018101266.
Graham, D. B., Jasso, G. J., Mok, A., Goel, G., Ng, A. C. Y., Kolde, R., et al. (2018). Nitric oxide engages an anti-inflammatory feedback loop mediated by peroxiredoxin 5 in phagocytes. Cell Reports, 24(4), 838–850. https://doi.org/10.1016/j.celrep.2018.06.081.
Kim, M. H., Lee, H. J., Lee, S. R., Lee, H. S., Huh, J. W., Bae, Y. C., et al. (2019). Peroxiredoxin 5 inhibits glutamate-induced neuronal cell death through the regulation of calcineurin-dependent mitochondrial dynamics in HT22 Cells. Molecular and Cellular Biology. https://doi.org/10.1128/MCB.00148-19.
Kim, M. H., Park, S. J., Kim, J. H., Seong, J. B., Kim, K. M., Woo, H. A., et al. (2018). Peroxiredoxin 5 regulates adipogenesis-attenuating oxidative stress in obese mouse models induced by a high-fat diet. Free Radical Biology and Medicine, 123, 27–38. https://doi.org/10.1016/j.freeradbiomed.2018.05.061.
Kim, M. H., Seong, J. B., Huh, J. W., Bae, Y. C., Lee, H. S., & Lee, D. S. (2019). Peroxiredoxin 5 ameliorates obesity-induced non-alcoholic fatty liver disease through the regulation of oxidative stress and AMP-activated protein kinase signaling. Redox Biology, 28, 101315. https://doi.org/10.1016/j.redox.2019.101315.
Wang, X., Phelan, S. A., Petros, C., Taylor, E. F., Ledinski, G., Jurgens, G., et al. (2004). Peroxiredoxin 6 deficiency and atherosclerosis susceptibility in mice: Significance of genetic background for assessing atherosclerosis. Atherosclerosis, 177(1), 61–70. https://doi.org/10.1016/j.atherosclerosis.2004.06.007.
Phelan, S. A., Wang, X., Wallbrandt, P., Forsman-Semb, K., & Paigen, B. (2003). Overexpression of Prdx6 reduces H2O2 but does not prevent diet-induced atherosclerosis in the aortic root. Free Radical Biology and Medicine, 35(9), 1110–1120.
Pacifici, F., Arriga, R., Sorice, G. P., Capuani, B., Scioli, M. G., Pastore, D., et al. (2014). Peroxiredoxin 6, a novel player in the pathogenesis of diabetes. Diabetes, 63(10), 3210–3220. https://doi.org/10.2337/db14-0144.
Fisher, A. B. (2017). Peroxiredoxin 6 in the repair of peroxidized cell membranes and cell signaling. Archives of Biochemistry and Biophysics, 617, 68–83. https://doi.org/10.1016/j.abb.2016.12.003.
Manevich, Y., Sweitzer, T., Pak, J. H., Feinstein, S. I., Muzykantov, V., & Fisher, A. B. (2002). 1-Cys peroxiredoxin overexpression protects cells against phospholipid peroxidation-mediated membrane damage. Proceedings of the National Academy of Sciences of the United States of America, 99(18), 11599–11604. https://doi.org/10.1073/pnas.182384499.
Kuda, O., Brezinova, M., Silhavy, J., Landa, V., Zidek, V., Dodia, C., et al. (2018). Nrf2-mediated antioxidant defense and peroxiredoxin 6 are linked to biosynthesis of palmitic acid ester of 9-hydroxystearic acid. Diabetes, 67(6), 1190–1199. https://doi.org/10.2337/db17-1087.
Yore, M. M., Syed, I., Moraes-Vieira, P. M., Zhang, T., Herman, M. A., Homan, E. A., et al. (2014). Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects. Cell, 159(2), 318–332. https://doi.org/10.1016/j.cell.2014.09.035.
Syed, I., Lee, J., Moraes-Vieira, P. M., Donaldson, C. J., Sontheimer, A., Aryal, P., et al. (2018). Palmitic acid hydroxystearic acids activate GPR40, which is involved in their beneficial effects on glucose homeostasis. Cell Metabolism, 27(2), 419–27 e4. https://doi.org/10.1016/j.cmet.2018.01.001.
Chatterjee, S., Feinstein, S. I., Dodia, C., Sorokina, E., Lien, Y. C., Nguyen, S., et al. (2011). Peroxiredoxin 6 phosphorylation and subsequent phospholipase A2 activity are required for agonist-mediated activation of NADPH oxidase in mouse pulmonary microvascular endothelium and alveolar macrophages. Journal of Biological Chemistry, 286(13), 11696–11706. https://doi.org/10.1074/jbc.M110.206623.
Vazquez-Medina, J. P., Dodia, C., Weng, L., Mesaros, C., Blair, I. A., Feinstein, S. I., et al. (2016). The phospholipase A2 activity of peroxiredoxin 6 modulates NADPH oxidase 2 activation via lysophosphatidic acid receptor signaling in the pulmonary endothelium and alveolar macrophages. FASEB Journal, 30(8), 2885–2898. https://doi.org/10.1096/fj.201500146R.
Vazquez-Medina, J. P., Tao, J. Q., Patel, P., Bannitz-Fernandes, R., Dodia, C., Sorokina, E. M., et al. (2019). Genetic inactivation of the phospholipase A2 activity of peroxiredoxin 6 in mice protects against LPS-induced acute lung injury. American Journal of Physiology-Lung Cellular and Molecular Physiology, 316(4), L656–L668. https://doi.org/10.1152/ajplung.00344.2018.
Hiroi, M., Nagahara, Y., Miyauchi, R., Misaki, Y., Goda, T., Kasezawa, N., et al. (2011). The combination of genetic variations in the PRDX3 gene and dietary fat intake contribute to obesity risk. Obesity (Silver Spring), 19(4), 882–887. https://doi.org/10.1038/oby.2010.275.
Funding
Not applicable.
Author information
Authors and Affiliations
Contributions
All authors have read and approved the submission of the manuscript to Cardiovascular Toxicology.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no conflicts of interest.
Ethical Approval
Writing and submission of this manuscript is in full compliance with pertinent ethical standards of scholarly publishing, including authorship and proper citation of references.
Additional information
Handling Editor: Kurt J. Varner.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Li, Y.R., Zhu, H. & Danelisen, I. Role of Peroxiredoxins in Protecting Against Cardiovascular and Related Disorders. Cardiovasc Toxicol 20, 448–453 (2020). https://doi.org/10.1007/s12012-020-09588-0
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12012-020-09588-0