Reduced Cerebral Blood Flow but Elevated Cerebral Glucose Metabolic Rate in Erythropoietin Overexpressing Transgenic Mice with Excessive Erythrocytosis

Frietsch, Thomas; Maurer, Martin H.; Vogel, Johannes; Gassmann, Max; Kuschinsky, Wolfgang; Waschke, Klaus F.

doi:10.1038/sj.jcbfm.9600360

Cited by 36 publications

(38 citation statements)

References 32 publications

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“…Irrespective of the problems associated with EPO abuse and gene doping [74], EPO has been correlated with the alteration of red cell membrane properties leading to a cognitive decrement in rodent animal models [2,3]. In addition, development of potentially detrimental side-effects during EPO therapy, such as for cerebral ischemia with increased metabolic rate and blood viscosity [75], could severely limit or halt the use of EPO for neurovascular diseases. As a result, alternate strategies have been suggested.…”

Section: Future Directions For Clinical Efficacy Safety and Toxicitmentioning

confidence: 99%

Raves and risks for erythropoietin

Maiese

Chong²,

Shang³

2008

Cytokine & Growth Factor Reviews

125

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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. Keywordsangiogenesis; cardiac; diabetes; erythropoietin; neurodegeneration Historical Background for ErythropoietinInitially 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 demonstrated similar findings that plasma from animals that were bled would yield a significant reticulocytosis. Interestingly, more elegant experiments later demonstrated that a rise in hemoglobin levels with reticulocytosis occurred in parabiotic rats when only one partner was exposed to hypoxia, illustrating that depressed oxygen tensions could stimulate EPO production. Eventually, human EPO protein was purified that paved the way for the cloning of the EPO gene and the development of recombinant EPO for clinical use [2,3]. *Corresponding Author: Kenneth Maiese, MD, Department of Neurology, 8C-1 UHC, Wayne State University School of Medicine, 4201 St. Antoine, Detroit,; email: aa2088@wayne.edu, kmaiese@med.wayne.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. The production and secretion of the mature EPO also relies upon the integrity of the N-and O-linked chains. The EPO gene is located on chromosome 7, exists as a single copy in a 5.4 kb region of the genomic DNA, and encodes a polypeptide chain containing 193 amino acids. During the production and secretion of EPO, a 166 amino acid peptide is initially generated following the cleavage of a 27 amino acid hydrophobic secretory leader ...

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Section: Future Directions For Clinical Efficacy Safety and Toxicitmentioning

confidence: 99%

Raves and risks for erythropoietin

Maiese

Chong²,

Shang³

2008

Cytokine & Growth Factor Reviews

125

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“…As tg6 mice developed excessive erythrocytosis that nearly doubled their arterial oxygen content, 23 we speculated that tg6 erythrocytes suffer from oxidative damage. Thus, we measured the nonprotein thiols in tg6 and wt erythrocytes.…”

Section: Assessment Of Properties Typical For Senescent Erythrocytesmentioning

confidence: 99%

Enhanced erythro-phagocytosis in polycythemic mice overexpressing erythropoietin

Bogdanova

Mihov

Lutz

et al. 2007

Blood

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Adaptive mechanisms to hematocrit levels of 0.9 in our erythropoietin-overexpressing mice (tg6) include increased plasma nitric oxide levels and erythrocyte flexibility. Doubled reticulocyte counts in tg6 suggest an increased erythrocyte turnover. Here we show that compared with wild-type (wt) animals, erythrocyte lifespan in tg6 is 70% lower in tg6 mice. Transgenic mice have a younger erythrocyte population as indicated by higher intercellular water and potassium content, higher flexibility, decreased density, increased surface to volume ratio, and decreased osmotic fragility. Interestingly, despite being younger, the tg6 erythrocyte population also harbors characteristics of accelerated aging such as an increased band 4.1a to 4.1b ratio, signs of oxidative stress, or decreased surface CD47 and sialic acids. In tg6, in vivo tracking of PKH26-labeled erythrocytes revealed dramatically increased erythrocyte incorporation by their liver macrophages. In vitro experiments showed that tg6 macrophages are more active than wt macrophages and that tg6 erythrocytes are more attractive for macrophages than wt ones. In conclusion, in tg6 mice erythrocyte aging is accelerated, which results, together with an increased number and activity of their macrophages, in enhanced erythrocyte clearance. Our data points toward a new mechanism downregulating red cell mass in excessive erythrocytosis in mice. IntroductionDuring aging, the erythrocytes considerably change the internal ion and protein composition, and the biomechanical and biochemical properties of their cell membrane, as well as size, shape, and surface to volume ratio. In humans, these changes finally result in selective elimination of senescent erythrocytes from the circulation. 1 The clearance of erythrocytes in mice and rabbits is in part age dependent and in part random. 2 Nevertheless, the agedependent erythrocyte clearance in these mammals is well controlled, involving oxidative damage, phosphatidylserine exposure, 3,4 desialylation, 5 and immunoglobulins. 6 The involvement of immunoglobulins in clearance of senescent erythrocytes in mice must, however, differ from that in humans, because naturally occurring antibodies in mice are exclusively of the IgM class. Under pathological conditions such as sickle cell anemia the phosphatidylserine exposure to the outer leaflet of the red cell membrane presumably plays a predominant role since in this disease the percentage of phosphatidylserine-expressing red cells is increased 2-to 10-fold. 4 Our transgenic (tg6) mice that constitutively overexpress human Epo in an oxygen-independent manner have a 12-fold elevated Epo plasma level 7 leading to hematocrit values of up to 0.9. As to the question how tg6 mice cope with excessive erythrocytosis, we reported earlier that they show chronic vasodilatation due to excessive NO production 7 and regulate blood viscosity by elevating erythrocyte flexibility. 8 Here we were especially interested to define the process of erythrocyte turnover in tg6 animals by focusing on mechanisms of...

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“…Irrespective of the problems associated with EPO abuse and gene doping (Baoutina et al, 2007;Diamanti-Kandarakis et al, 2005;Segura et al, 2007), EPO has been correlated with the alteration of red cell membrane properties leading to a cognitive decrement in rodent animal models (Li et al, 2004a;. In addition, development of potentially detrimental side-effects during EPO therapy, such as for cerebral ischemia with increased metabolic rate and blood viscosity (Frietsch et al, 2007), could severely limit or halt the use of EPO for neurovascular diseases. As a result, alternate strategies have been suggested.…”

Section: Future Perspectives and Considerations For Epomentioning

confidence: 99%

Erythropoietin: Elucidating new cellular targets that broaden therapeutic strategies

Maiese

Chong

et al. 2008

Progress in Neurobiology

102

155

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Given that erythropoietin (EPO) is no longer believed to have exclusive biological activity in the hematopoietic system, EPO is now considered to have applicability in a variety of nervous system disorders that can overlap with vascular disease, metabolic impairments, and immune system function. As a result, EPO may offer efficacy for a broad number of disorders that involve Alzheimer's disease, cardiac insufficiency, stroke, trauma, and diabetic complications. During a number of clinical conditions, EPO is robust and can prevent metabolic compromise, neuronal and vascular degeneration, and inflammatory cell activation. Yet, use of EPO is not without its considerations especially in light of frequent concerns that may compromise clinical care. Recent work has elucidated a number of novel cellular pathways governed by EPO that can open new avenues to avert deleterious effects of this agent and offer previously unrecognized perspectives for therapeutic strategies. Obtaining greater insight into the role of EPO in the nervous system and elucidating its unique cellular pathways may provide greater cellular viability not only in the nervous system but also throughout the body.

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Reduced Cerebral Blood Flow but Elevated Cerebral Glucose Metabolic Rate in Erythropoietin Overexpressing Transgenic Mice with Excessive Erythrocytosis

Cited by 36 publications

References 32 publications

Raves and risks for erythropoietin

Raves and risks for erythropoietin

Enhanced erythro-phagocytosis in polycythemic mice overexpressing erythropoietin

Erythropoietin: Elucidating new cellular targets that broaden therapeutic strategies

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