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Raves and risks for erythropoietin

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Abstract

Global use of erythropoietin (EPO) continues to increase as a proven agent for the treatment of anemia. Yet, EPO is no longer believed to have exclusive biological activity in the hematopoietic system and is now considered applicable for a variety of disorders such as diabetes, Alzheimer's disease, and cardiovascular disease. Treatment with EPO is considered to be robust and can prevent metabolic compromise, neuronal and vascular degeneration, and inflammatory cell activation. On the converse side, observations that EPO administration is not without risk have fueled controversy. Here we present recent advances that have elucidated a number of novel cellular pathways governed by EPO to open new therapeutic avenues for this agent and avert its potential deleterious effects.

Section snippets

Historical background for erythropoietin

Initially termed “hemopoietine”, erythropoietin (EPO) became evident as a factor that could stimulate new red blood cell development through the pioneering studies of Carnot and Deflandre in 1906 [1]. This team of investigators demonstrated that plasma removed from rabbits following a bleeding stimulus that was later injected into control untreated rabbits would lead to the development of immature red blood cells, or reticulocytosis. A number of other investigators followed these studies that

Structural and molecular determinants of erythropoietin activity

EPO is a 30.4 kDa glycoprotein with approximately half of its molecular weight derived from carbohydrates that can vary among species [3]. EPO contains four glycosylated chains including three N-linked and one O-linked acidic oligosaccharide side chains. The glycosylated chains are important for the biological activity of EPO and can protect EPO from oxygen radical degradation. The presence of the carbohydrates also are important in the control of the metabolism of EPO, since EPO molecules with

Cellular expression and signaling for erythropoietin and its receptor

EPO is considered to be ubiquitous in the body, since this trophic factor can be detected in the breath of healthy individuals [4], [5]. In addition, it has been suggested that EPO may provide developmental cognitive support in humans with the recent observation that elevated EPO concentrations during infant maturation have been correlated with increased mental development index scores [6]. The primary organs of EPO production and secretion are the kidney, liver, brain, and uterus (Table 1).

Diabetes and EPO

Diabetes mellitus (DM) is found in at least 16 million individuals in the United States and more than 165 million individuals worldwide [5]. Furthermore, by the year 2030, it is predicted that more than 360 million individuals will be afflicted with DM and its debilitating conditions [4]. Type 2 DM represents at least 80% of all diabetics and is dramatically increasing in incidence as a result of changes in human behavior and increased body mass index. Type 1 insulin-dependent diabetes mellitus

Oxidative stress, apoptosis, and EPO

EPO modulates a variety of signal transduction pathways for cytoprotection that can involve protein kinase B, signal transducer and activator of transcription pathways, forkhead transcription factors, caspases, and nuclear factor-κB (Fig. 1). Intimately linked to these cell longevity pathways with EPO are the injury mechanisms associated with oxidative stress and apoptosis. Oxidative stress represents a significant mechanism for the destruction of cells that can involve apoptotic cell injury.

Future directions for clinical efficacy, safety, and toxicity of erythropoietin

In light of the multiple cytoprotective pathways that are governed by EPO, it may come as no surprise that EPO has been identified as a possible candidate for a number of disease entities that involve cardiac, nervous, and vascular system diseases. At present, there are at least 100 trials with the National Institutes of Health website (http://www.clinicaltrials.gov) that are either recruiting or in preparation to examine the clinical effects of EPO in patients with a variety of disorders that

Acknowledgments

We apologize to our colleagues whose work we were unable to cite as a result of article space limitations. This research was supported by the following grants (KM): American Diabetes Association, American Heart Association (National), Bugher Foundation Award, Janssen Neuroscience Award, LEARN Foundation Award, MI Life Sciences Challenge Award, Nelson Foundation Award, NIH NIEHS (P30 ES06639), and NIH NINDS/NIA.

Kenneth Maiese is a physician-scientist whose interests focus on the basic and clinical mechanisms that control cellular plasticity and longevity as well as inflammatory mechanisms in the nervous and vascular systems. He is presently the Director of the Division of Cellular and Molecular Cerebral Ischemia and is Professor in Neurology, Anatomy & Cell Biology, Molecular Medicine, the Institute of Environmental Health Sciences, and the Barbara Ann Karmanos Cancer Institute at Wayne State

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    Kenneth Maiese is a physician-scientist whose interests focus on the basic and clinical mechanisms that control cellular plasticity and longevity as well as inflammatory mechanisms in the nervous and vascular systems. He is presently the Director of the Division of Cellular and Molecular Cerebral Ischemia and is Professor in Neurology, Anatomy & Cell Biology, Molecular Medicine, the Institute of Environmental Health Sciences, and the Barbara Ann Karmanos Cancer Institute at Wayne State University School of Medicine. Dr. Maiese graduated from the University of Pennsylvania Suma cum Laude with Distinction and received his medical degree as a Teagle and Grupe Foundation Scholar from Weill Medical College of Cornell University. He obtained his internship and residency at The New York Hospital-Cornell Medical Center, subsequently completed his clinical and basic science postdoctoral training at Cornell and the National Institute of Aging, then joined the faculty of Weill Medical College of Cornell University. His investigations are designed to translate basic science into successful therapeutic treatments for conditions such as metabolic disorders, cardiovascular disease, diabetes, stroke, and Alzheimer's disease. To highlight some of his accomplishments, Dr. Maiese has been cited early in his career with several young scientist awards and his work has received the distinction by the National Institutes of Health as being “High-Impact Research and Potential Public Health Benefit” with continuous funding from numerous sources that include the American Diabetes Association, the American Heart Association, the Bugher Foundation, a Johnson and Johnson Focused Giving Award, and the National Institutes of Health. Dr. Maiese also has been fortunate to receive recognition with outstanding teaching awards and election to America's Top Physicians and The Best of U.S. Physicians. He chairs national grant committees and is a chartered panel member or consultant for several national and international foundations as well as multiple study sections and special emphasis panels for the National Institutes of Health. He serves as the Editor-in-Chief for two international journals as well as an Associate Editor or a member of the editorial board for several journals, executive committees, technology transfer panels, and scientific advisory councils. Given the broad applications of his work, Dr. Maiese is frequently honored as the chairperson and/or the plenary speaker for a number of international symposiums in a range of disciplines that include cell biology, neuroscience, vascular biology, cardiac disease, molecular oncology, drug discovery, and renal physiology.

    Zhao Zhong Chong is a Research Assistant Professor in the Division of Cellular and Molecular Cerebral Ischemia and the Department of Neurology whose research is directed upon the molecular mediators of cellular protection and inflammation. Dr. Chong received his undergraduate training from Binzhou Medical College, his Masters degree from Chongqing University of Medical Science, and his MD and PhD degrees from Peking Union Medical College. Dr. Chong initially concentrated his work on neuroprotective mechanisms in the brain which has led to the development of novel agents to prevent thrombosis in both the heart and the brain. In the Division of Cellular and Molecular Cerebral Ischemia, Dr. Chong subsequently has characterized the role of specific kinases that are responsible for both the maintenance and destruction of DNA in both vascular and neuronal cells. His work has led to multiple publications and presentations at international meetings. Dr. Chong has broadened his translational research efforts with his focus upon unique cell receptor systems in the nervous and vascular systems, such as those that involve erythropoietin and the metabotropic glutamate receptor system, to examine the specific genetic mechanisms that may be developed to formulate therapy for degenerative disorders of the neuronal and vascular systems.

    Yan Chen Shang is a Research Assistant in the Division of Cellular and Molecular Cerebral Ischemia who has considerable experience in working with primary cells, cell lines, and animal models of neuronal and vascular diseases. Ms. Shang received her undergraduate training from Shangdong University. Her interests center upon inflammatory cells of the body and their integration and participation in metabolic and degenerative disorders, such as diabetes mellitus. Ms. Shang's present work has further elucidated several components of cellular inflammation and the activation of phagocytic cells that can destroy viable cells in the brain.

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