Erythropoietin and Oxidative Stress

Abstract

Unmitigated oxidative stress can lead to diminished cellular longevity, accelerated aging, and accumulated toxic effects for an organism. Current investigations further suggest the significant disadvantages that can occur with cellular oxidative stress that can lead to clinical disability in a number of disorders, such as myocardial infarction, dementia, stroke, and diabetes. New therapeutic strategies are therefore sought that can be directed toward ameliorating the toxic effects of oxidative stress. Here we discuss the exciting potential of the growth factor and cytokine erythropoietin for the treatment of diseases such as cardiac ischemia, vascular injury, neurodegeneration, and diabetes through the modulation of cellular oxidative stress. Erythropoietin controls a variety of signal transduction pathways during oxidative stress that can involve Janus-tyrosine kinase 2, protein kinase B, signal transducer and activator of transcription pathways, Wnt proteins, mammalian forkhead transcription factors, caspases, and nuclear factor κB. Yet, the biological effects of erythropoietin may not always be beneficial and may be poor tolerated in a number of clinical scenarios, necessitating further basic and clinical investigations that emphasize the elucidation of the signal transduction pathways controlled by erythropoietin to direct both successful and safe clinical care. KeywordsAlzheimer's disease; Akt; angiogenesis; apoptosis; cancer; cardiac; caspases; diabetes; endothelial; erythropoietin; forkhead; FoxO; GSK-3β; inflammation; mitochondria; NF-κB; renal; STATs; Wnt OXIDATIVE STRESSInitial work in pathways that can lead to oxidative stress by early investigators observed that increased metabolic rates could be detrimental to animals in an elevated oxygen environment. More current studies point to the potential aging mechanisms and accumulated toxic effects for an organism that are tied to oxidative stress (Maiese, et al., 2008a NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript in organisms, or at least the rate of oxygen consumption in organisms, has intrigued several investigators. Pearl proposed that increased exposure to oxygen through an increased metabolic rate could lead to a shortened life span (Pearl, 1928). Subsequent work by multiple investigators has furthered this hypothesis by demonstrating that increased metabolic rates could be detrimental to animals in an elevated oxygen environment . When one moves to more current work, oxygen free radicals and mitochondrial DNA mutations have become associated with oxidative stress injury, aging mechanisms, and accumulated toxicity for an organism (Yui and Matsuura, 2006).Oxygen free radicals can be generated in elevated quantities during the reduction of oxygen and subsequently lead to cell injury and apoptosis. Oxidative stress occurs as a result of the development of reactive oxygen species that consist of oxygen free radicals and other chemical entities. These agents can involve superoxide free radicals, hydrogen peroxide, sin...

Correlation between erythropoietin serum levels and erythrocyte susceptibility to lipid peroxidation in elderly with type 2 diabetes

“…In basic experimental research and clinical studies, erythropoietin has been strongly associated with modulation of cellular metabolism (19,20). Diabetes mellitus, a major public health problem, comes also as main evidence when cellular dysfunction related to cell metabolism is under scrutiny (21).…”

“…Results obtained confirm observations of literature regarding the damaging effects of hyperglycemia mediated or stimulated by oxygen species. Mechanisms could be the following: 1) glucose oxidation pathways generate oxygen free radicals; 2) hyperglycemia deteriorates antioxidant capacity, and 3) mitochondria-derived reactive oxygen species is generated in hyperglycemic states (6,19,21).…”

“…Of late years it has been widely acknowledged that erythropoietin' s action is not limited to hemopoietic system, as erythropoietin involvement is being extensively evaluated in various pathological conditions concurrent with oxidative stress, vascular diseases, metabolic abnormalities or immune system dysfunction (19). Recent data of biomedical literature has shown that erythropoietin's pleiotropic actions are involved in normal and pathological ageing (18,20).…”

The Protective Role of Erythropoietin in the Developing Brain

“…A major mechanism of Epo-induced neuroprotection is its ability to prevent apoptosis (Byts & Sirén, 2009;Chen et al, 2007;Chong et al, 2005;Digicaylioglu & Lipton, 2001;Kaindl et al, 2008;Kumral et al, 2006;Ruscher et al, 2002;Sirén et al, 2001;Villa et al, 2003;Weber et al, 2002;Wen et al, 2002;Wu et al, 2007). Other mechanisms of Epo-induced neuroprotection include anti-inflammatory, anti-oxidative, anti-neurotoxic, angiogenic, neurotrophic effects, neural regeneration, prevention from edema and protecting the white matter (Agnello et al, 2002;Kertesz et al, 2004;Kumral et al, 2005a,b;Maiese et al, 2008a;Pankratova et al, 2010;Rabie & Marti, 2008;Shingo et al, 2001;Sifringer et al, 2009Sifringer et al, , 2010Solaroglu et al, 2003;van der Kooij et al, 2008;Wang et al, 2004;Zacharias et al, 2010).…”

“…The neonatal brain seems particularly vulnerable to oxidative injury because of immature scavenging mechanisms and a relative abundance of iron that acts as a catalyst for the formation of free radicals (Blomgren & Hagberg, 2006). Epo controls a variety of signal transduction pathways during oxidative stress that can involve Jak-2, Akt, STAT cascades, caspases, and NF-κB (Maiese et al, 2008a). Oxygen-induced cell death in the developing brain is associated with decreased GSH (reduced glutathione) and increased GSSG (oxidized glutathione) levels in which glutathione plays critical roles as an antioxidant (Bains and Shaw, 1997;Dringen, 2000), enzyme cofactor (Chance et al, 1979), cysteine storage form (Cooper and Kristal, 1997;Tateishi et al, 1977) and as a neuromodulator (Janáky et al, 1999) in the CNS.…”