Endogenous Erythropoietin Signaling Is Required for Normal Neural Progenitor Cell Proliferation

Chen, Zhi Yong; Asavaritikrai, Pundit; Prchal, Josef T.; Noguchi, Constance Tom

doi:10.1074/jbc.m701988200

Cited by 161 publications

(144 citation statements)

References 48 publications

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“…Targeted knockout of EpoR expression in the mouse brain has shown reduced neural cell proliferation and impaired poststroke neurogenesis (Tsai et al 2006). Although global deletion of EpoR is lethal to mouse embryos, rescue by expression of erythroid-specific EpoR results in survival to adulthood (Suzuki et al 2002) but impaired neural cell proliferation and viability (Chen et al 2007). In addition, administration of Epo protects against experimental brain injury in vivo (Sakanaka et al 1998;Brines et al 2000).…”

Section: Nonhematopoietic Effects Of Epomentioning

confidence: 99%

Erythropoietin

Bunn

2013

Cold Spring Harbor Perspectives in Medicine

210

171

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During the past century, few proteins have matched erythropoietin (Epo) in capturing the imagination of physiologists, molecular biologists, and, more recently, physicians and patients. Its appeal rests on its commanding role as the premier erythroid cytokine, the elegant mechanism underlying the regulation of its gene, and its remarkable impact as a therapeutic agent, arguably the most successful drug spawned by the revolution in recombinant DNA technology. This concise review will begin with a synopsis of the colorful history of this protein, culminating in its purification and molecular cloning. It then covers in more detail the contemporary understanding of Epo's physiology as well as its structure and interaction with its receptor. A major part of this article focuses on the regulation of the Epo gene and the discovery of HIF, a transcription factor that plays a cardinal role in molecular adaptation to hypoxia. In the concluding section, a synopsis of Epo's role in disorders of red blood cell production will be followed by an assessment of the remarkable impact of Epo therapy in the treatment of anemias, as well as concerns that provide a strong impetus for the development of even safer and more effective treatment.

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Section: Nonhematopoietic Effects Of Epomentioning

confidence: 99%

Erythropoietin

Bunn

2013

Cold Spring Harbor Perspectives in Medicine

210

171

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“…The TIMP-3 mRNA peaked at 48 h in both the cortex and hippocampus of that side. The higher TIMP-3 values seen in the contralateral hippocampus than in the contralateral cortex may also be due to secondary damage ( p < 0.05; mRNA T ¼ 48 h; protein, T ¼ 72 h), or perhaps the hippocampus was more susceptible to secondary damage from ischemia (Chen et al, 2007;Yamashita et al, 2007). The increases seen in the early period (peaks in mRNA and protein at 12 h and 24 h, respectively) in the ipsilateral hemisphere may due to direct mechanical damage, or perhaps the distance between the ipsilateral hippocampus and the damaged site (ipsilateral cortex) attenuated the increase, such that the increase in the ipsilateral hippocampus was significantly lower than that seen in the ipsilateral cortex ( p < 0.01).…”

Section: Effect Of Mild Hypothermia On Timp-3mentioning

confidence: 99%

The effect of hypothermia on the expression of TIMP-3 after traumatic brain injury in rats

Feng¹,

Jiang²,

Liang³

et al. 2009

Journal of Neurotrauma

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Here we investigate the effect of hypothermia on the expression of apoptosis-regulating protein TIMP-3 after fluid percussion traumatic brain injury (TBI) in rats. We began with 210 adult male Sprague-Dawley rats and randomly assigned them to three groups: TBI with hypothermia treatment (328C), TBI with normothermia (378C), and sham-injured controls. TBI was induced by a fluid percussion TBI device. Mild hypothermia (328C) was achieved by partial immersion in a water bath (08C) under general anesthesia for 4 h. The rats were killed at 4, 6, 12, 24, 48, and 72 h and 1 week after TBI. The mRNA and protein level of TIMP-3 in both the injured and uninjured hemispheres of the brains from each group were measured using RT-PCR and Western blotting. In the normothermic group, TIMP-3 levels in both the injured and uninjured hemispheres were significantly increased after TBI compared with those of sham-injured animals ( p < 0.01). In contrast, post-traumatic hypothermia significantly attenuated this increase. According to the RT-PCR and Western blot analyses, the maximum mRNA levels of TIMP-3 were reduced to 60.60 AE 2.30%, 55.83 AE 1.80%, 66.03 AE 2.10%, and 64.51 AE 1.50%, respectively, of the corresponding values in the normothermic group in the injured and uninjured hemispheres (cortex and hippocampus) of the hypothermia group ( p < 0.01), while the respective maximum protein levels of TIMP-3 were reduced to 57.50 AE 1.50, 52.67 AE 2.20, 60.31 AE 2.50 and 54.76 AE 1.40 ( p < 0.01). Our data suggest that moderate fluid percussion brain injury significantly upregulates TIMP-3 expression, and that this increase may be suppressed by hypothermia treatment.

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“…In vitro Epo has been shown to regulate a variety of neural functions such as calcium flux (Korbel et al, 2004) neurotransmitter synthesis and cell survival (Velly et al, 2010;Vogel et al, 2003). Furthermore Epo has neurotrophic effects (Chen et al, 2007;Grimm et al, 2002;Junk et al, 2002), can induce an angiogenic phenotype in cultured endothelial cells, is a potent angiogenic factor in vivo (Ribatti et al, 2003) and enhances ventilation in hypoxic conditions (Soliz et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Constitutive excessive erythrocytosis causes inflammation and increased vascular permeability in aged mouse brain

Ogunshola¹,

Moransard²,

Gassmann³

2013

Brain Research

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Excessive erythrocytosis results in severely increased blood viscosity that may compromise the vascular endothelium. Using our transgenic mouse model of excessive erythrocytosis we previously showed that despite altered brain endothelial cell morphology and an activated vasculature, brain vascular integrity was largely maintained up to 4-5 months of age. We now present data showing that persistent long-term damage of the vascular wall during the later stages of adulthood (9-10 months) results in a chronic detrimental inflammatory phenotype and increased vessel permeability that likely contributes to the reduced life span of our erythropoietin overexpressing transgenic mouse. In aged transgenic animals inflammatory cells were detected in brain tissue and elevated RNA and protein levels of inflammatory markers such as IL-6 and TNF were observed in both brain tissue and blood plasma. Additionally, increased expression of p53 and other pro-apoptotic markers, as well as decreased Bcl-xL expression in the brain vasculature, indicated ongoing cell death within the vascular compartment. Finally, abnormally elevated vascular permeability in all organs was detected in correlation with decreased expression of the tight junction protein occludin and the adherens junction protein -catenin in brain. Thus chronic erythrocytosis results in sustained activation of inflammatory pathways, vascular dysfunction and bloodbrain barrier disruption.

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Endogenous Erythropoietin Signaling Is Required for Normal Neural Progenitor Cell Proliferation

Cited by 161 publications

References 48 publications

Erythropoietin

Erythropoietin

The effect of hypothermia on the expression of TIMP-3 after traumatic brain injury in rats

Constitutive excessive erythrocytosis causes inflammation and increased vascular permeability in aged mouse brain

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