SurveyRaves and risks for erythropoietin
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
References (80)
- et al.
Erythropoietin in the brain: can the promise to protect be fulfilled?
Trends Pharmacol Sci
(2004) - et al.
Erythropoietin and treatment of non-anemic conditions—cardiovascular protection
Semin Hematol
(2007) - et al.
Erythropoietin modulation of podocalyxin and a proposed erythroblast niche
Blood
(2007) - et al.
The interaction between heart failure and other heart diseases, renal failure, and anemia
Semin Nephrol
(2006) - et al.
Positive effect of darbepoetin on peri-infarction remodeling in a porcine model of myocardial ischemia-reperfusion
J Mol Cell Cardiol
(2007) - et al.
The role of erythropoietin in central and peripheral nerve injury
Clin Neurol Neurosurg
(2007) - et al.
Recombinant human erythropoietin decreases myeloperoxidase and caspase-3 activity and improves early functional results after spinal cord injury in rats
J Clin Neurosci
(2007) - et al.
Neuroprotective effects of erythropoietin in the rat hippocampus after pilocarpine-induced status epilepticus
Neurobiol Dis
(2007) - et al.
Akt1 drives endothelial cell membrane asymmetry and microglial activation through Bcl-x(L) and caspase 1, 3 and 9
Exp Cell Res
(2004) - et al.
Podocyte protection by darbepoetin: preservation of the cytoskeleton and nephrin expression
Kidney Int
(2007)
Oxidative stress in the brain: novel cellular targets that govern survival during neurodegenerative disease
Prog Neurobiol
A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span
Cell
Regulation of FOXO3a/beta-catenin/GSK-3beta signaling by 3,3′-diindolylmethane contributes to inhibition of cell proliferation and induction of apoptosis in prostate cancer cells
J Biol Chem
Cellular demise and inflammatory microglial activation during beta-amyloid toxicity are governed by Wnt1 and canonical signaling pathways
Cell Signal
Wnts: up-and-coming at the synapse
Trends Neurosci
GSK-3 is a viable potential target for therapeutic intervention in bipolar disorder
Neurosci Biobehav Rev
Erythropoietin modulates the anticancer activity of chemotherapeutic drugs in a murine lung cancer model
Cancer Lett
Long-term expression of erythropoietin from myoblasts immobilized in biocompatible and neovascularized microcapsules
Mol Ther
In vivo evaluation of EPO-secreting cells immobilized in different alginate-PLL microcapsules
J Control Release
Intranasal recombinant human erythropoietin protects rats against focal cerebral ischemia
Neurosci Lett
Sur l’activite hemopoietique de serum au cours de la regeneration du sang
C R Acad Sci (Paris)
New avenues of exploration for erythropoietin
JAMA
Mechanisitic insights into diabetes mellitus and oxidative stress
Curr Med Chem
Oxidative stress biology and cell injury during type 1 and type 2 diabetes mellitus
Curr Neurovasc Res
Erythropoietin concentrations and neurodevelopmental outcome in preterm infants
Pediatrics
Erythropoietin reduces ischemia-reperfusion injury in the rat liver
Eur Surg Res
Brain erythropoietin receptor expression in Alzheimer disease and mild cognitive impairment
J Neuropathol Exp Neurol
Erythropoietin improves anemia exercise tolerance and renal function and reduces B-type natriuretic peptide and hospitalization in patients with heart failure and anemia
Am Heart J
Erythropoietin-induced neurovascular protection, angiogenesis, and cerebral blood flow restoration after focal ischemia in mice
J Cereb Blood Flow Metab
An extracellular region of the erythropoietin receptor of the subterranean blind mole rat Spalax enhances receptor maturation
Proc Natl Acad Sci USA
High amniotic fluid erythropoietin levels are associated with an increased frequency of fetal and neonatal morbidity in type 1 diabetic pregnancies
Diabetologia
Vascular injury during elevated glucose can be mitigated by erythropoietin and Wnt signaling
Curr Neurovasc Res
Erythropoietin involves the phosphatidylinositol 3-kinase pathway, 14-3-3 protein and FOXO3a nuclear trafficking to preserve endothelial cell integrity
Br J Pharmacol
Darbepoetin alfa, a long-acting erythropoietin analog, offers novel and delayed cardioprotection for the ischemic heart
Am J Physiol Heart Circ Physiol
Erythropoietin is a novel vascular protectant through activation of Akt1 and mitochondrial modulation of cysteine proteases
Circulation
Erythropoietin fosters both intrinsic and extrinsic neuronal protection through modulation of microglia, Akt1, Bad, and caspase-mediated pathways
Br J Pharmacol
Erythropoietin prevents early and late neuronal demise through modulation of Akt1 and induction of caspase 1, 3 and 8
J Neurosci Res
The effect of recombinant human erythropoietin on neurovasculature repair after focal ischemic stroke in neonatal rats
J Pharmacol Exp Ther
Microglial integrity is maintained by erythropoietin through integration of Akt and its substrates of glycogen synthase kinase-3beta, beta-catenin, and nuclear factor-kappaB
Curr Neurovasc Res
Apaf-1, Bcl-xL, cytochrome c, and caspase-9 form the critical elements for cerebral vascular protection by erythropoietin
J Cereb Blood Flow Metab
Cited by (0)
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.