Erythropoietin and hypoxia stimulate erythropoietin receptor and nitric oxide production by endothelial cells

Beleslin-Čokić, Bojana B.; Čokić, Vladan P.; Yu, Xiaobing; Weksler, Babette B.; Schechter, Alan N.; Noguchi, Constance Tom

doi:10.1182/blood-2004-02-0744

Cited by 262 publications

(241 citation statements)

References 51 publications

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“…Other HIF-regulated genes were examined by quantitative real-time PCR, including Epo receptor (EpoR), glucokinase (Gck), pyruvate dehydrogenase kinase 1 (Pdk1), and lactate dehydrogenase (Ldha) in islets of RIPcre þ vhlh fl/fl and wild-type mice. In keeping with previous reports, 28,29 gene expression of EpoR, Pdk1, and Ldha were upregulated, whereas Gck trended lower in islets of RIPcre þ vhlh fl/fl mice compared with wild-type mice ( Figure 9). …”

Section: Resultssupporting

confidence: 92%

Vhl is required for normal pancreatic β cell function and the maintenance of β cell mass with age in mice

Choi

Cai

Schroer

et al. 2011

Laboratory Investigation

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Type 2 diabetes is hallmarked by insulin resistance and insufficient b-cell function. Islets of type 2 diabetes patients have been shown to have decreased hypoxia-inducible factor (HIF)-1a/b expression. Target genes of the HIF pathway are involved in angiogenesis, survival, proliferation, and energy metabolism, and von Hippel-Lindau protein (VHL) is a negative regulator of this pathway. We hypothesized that increased HIF-mediated gene transcription by VHL deletion in the b-cells would increase b-cell mass and function. We generated b-cell-specific VHL-knockout mice using the Cre-loxP recombination system driven by the rat insulin promoter to assess the role of VHL in glucose homeostasis and b-cell function. VHL deletion in the pancreatic b-cells led to impaired glucose tolerance due to defects in glucose-stimulated insulin secretion and b-cell mass with age. VHL-knockout islets had decreased GLUT2, but increased glucose transporter 1 and vascular endothelial growth factor expression. Furthermore, there were significant aberrations in islet morphology in the VHL-knockout mice, likely due to increased islet vasculature. Given that erythropoietin (EPO) is a target gene of the HIF pathway, which is not expressed in islets, we tested whether activating EPO signaling by systemic administration with recombinant human EPO (rHuEPO) can overcome the b-cell defects that occurred with VHL loss. We observed improved glucose tolerance and restoration of GLUT2 expression in VHL-deficient b-cells in response to rHuEPO. Contrary to our hypothesis, loss of VHL and increased transcription of HIF-target genes resulted in impaired b-cell function and mass, which can be overcome with exogenous EPO. Our results indicate a critical role for VHL in b-cell function and mass, and that EPO administration improved b-cell function making it a potential strategy for diabetes treatment. KEYWORDS: angiogenesis; b-cell; diabetes mellitus; GLUT2; hypoxia-inducible factor; insulin secretion; von Hippel-Lindau Type 2 diabetes is a disease that is now considered epidemic, as it affects over 200 million people globally, and its prevalence continues to rise despite advances in treatment. 1,2 The two hallmark characteristics of type 2 diabetes are insulin resistance and b-cell dysfunction. 3,4 Under insulin-resistant conditions, b-cells undergo a compensation process by expanding b-cell mass and enhancing b-cell function. When b-cell compensation can adequately meet the insulin demands of the body, normoglycemia is maintained. 5-7 However, in susceptible individuals perhaps with genetic defects and/or environmental insults, the b-cells cannot meet the metabolic demands, ultimately resulting in type 2 diabetes. [8][9][10][11] A previous study by Gunton et al 12 reported results of gene expression profiling analyses on islets of humans with type 2 diabetes, and found a significant decrease in aryl-hydrocarbon-receptor nuclear translocator (ARNT)/hypoxiainducible factor-1b (HIF-1b) expression in these islets. 12 Concomitant with the decrease in ARNT expre...

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Section: Resultssupporting

confidence: 92%

Vhl is required for normal pancreatic β cell function and the maintenance of β cell mass with age in mice

Choi

Cai

Schroer

et al. 2011

Laboratory Investigation

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“…Similarly, Epo did not increase the production of secondary neurospheres in adult NPC cultures supplemented with EGF (7) suggesting that Epo response may be more apparent during stress. In muscle and endothelial progenitor cell cultures, we observed maximal effects of Epo when proliferating progenitor cells were cultured under stress or suboptimal conditions of low serum or low oxygen tension (3,5), providing further evidence that Epo may be an important stress responder. In addition, anti-Epo antibodies reduced NPC neurogenesis in cultures exposed to hypoxia, but had little or no effect in control cultures (7).…”

Section: Discussionmentioning

confidence: 55%

“…EpoR-null mice and Epo-null mice die in utero because of lack of mature red blood cell production (1,2). However, functional EpoR has been identified in non-erythroid cells such as endothelial, muscle, and neural cells, and there is increasing evidence that Epo can act to stimulate cell proliferation, cell-specific function or promote cell survival in these tissues (3)(4)(5)(6)(7)(8). In culture, astrocytes and neurons up-regulate Epo and EpoR expression in response to hypoxia (8 -10).…”

Section: Epomentioning

confidence: 99%

Endogenous Erythropoietin Signaling Is Required for Normal Neural Progenitor Cell Proliferation

Chen

Asavaritikrai

Prchal

et al. 2007

Journal of Biological Chemistry

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161

138

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Erythropoietin (Epo) and its receptor (EpoR), critical for erythropoiesis, are expressed in the nervous system. Prior to death in utero because of severe anemia EpoR-null mice have fewer neural progenitor cells, and differentiated neurons are markedly sensitive to hypoxia, suggesting that during development Epo stimulates neural cell proliferation and prevents neuron apoptosis by promoting oxygen delivery to brain or by direct interaction with neural cells. Here we present evidence that neural progenitor cells express EpoR at higher levels compared with mature neurons; that Epo stimulates proliferation of embryonic neural progenitor cells; and that endogenous Epo contributes to neural progenitor cell proliferation and maintenance. EpoRnull mice were rescued with selective EpoR expression driven by the endogenous EpoR promoter in hematopoietic tissue but not in brain. Although these mice exhibited normal hematopoiesis and erythrocyte production and survived to adulthood, neural cell proliferation and viability were affected. Embryonic brain exhibited increased neural cell apoptosis, and neural cell proliferation was reduced in the adult hippocampus and subventricular zone. Neural cells from these animals were more sensitive to hypoxia/glutamate neurotoxicity than normal neurons in culture and in vivo. These observations demonstrate that endogenous Epo/EpoR signaling promotes cell survival in embryonic brain and contributes to neural cell proliferation in adult brain in regions associated with neurogenesis. Therefore, Epo exerts extrahematopoietic function and contributes directly to brain development, maintenance, and repair by promoting cell survival and proliferation independent of insult, injury, or ischemia.

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“…Another critical but unexplored question concerning intervention with tissue protective cytokines in myocardial ischemia is information on the optimum dose. This issue is especially critical because EPO has been shown to exhibit an inverted U-shaped dose-response curve in a number of experimental systems, e.g., EPO-mediated endothelial cell nitric oxide (NO) production (34), such that high doses of EPO lose biological activity. Furthermore, because EPO has been shown in the nervous system to require only a brief presence to trigger protective functions (2), further study will be needed to determine whether peak serum concentrations or area under the concentration curve is the important variable.…”

Section: Discussionmentioning

confidence: 99%

A nonerythropoietic derivative of erythropoietin protects the myocardium from ischemia–reperfusion injury

Fiordaliso

Chimenti

Staszewsky

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

201

134

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The cytokine erythropoietin (EPO) protects the heart from ischemic injury, in part by preventing apoptosis. However, EPO administration can also raise the hemoglobin concentration, which, by increasing oxygen delivery, confounds assignment of cause and effect. The availability of EPO analogs that do not bind to the dimeric EPO receptor and lack erythropoietic activity, e.g., carbamylated EPO (CEPO), provides an opportunity to determine whether EPO possesses direct cardioprotective activity. In vivo, cardiomyocyte loss after experimental myocardial infarction (MI) of rats (40 min of occlusion with reperfusion) was reduced from Ϸ57% in MI-control to Ϸ45% in animals that were administered CEPO daily for 1 week (50 g͞kg of body weight s.c.) with the first dose administered intravenously 5 min before reperfusion. CEPO did not increase the hematocrit, yet it prevented increases in left ventricular (LV) end-diastolic pressure, reduced LV wall stress in systole and diastole, and improved LV response to dobutamine infusion compared with vehicle-treated animals. In agreement with the cardioprotective effect observed in vivo, staurosporineinduced apoptosis of adult rat or mouse cardiomyocytes in vitro was also significantly attenuated (Ϸ35%) by CEPO, which is comparable with the effect of EPO. These data indicate that prevention of cardiomyocyte apoptosis, in the absence of an increase in hemoglobin concentration, explains EPO's cardioprotection. Nonerythropoietic derivatives such as CEPO, devoid of the undesirable effects of EPO, e.g., thrombogenesis, could represent safer and more effective alternatives for treatment of cardiovascular diseases, such as MI and heart failure. Furthermore, these findings expand the activity spectrum of CEPO to tissues outside the nervous system. apoptosis ͉ cardioprotection ͉ cytokine ͉ tissue injury E rythropoietin (EPO) protects the brain and the spinal cord from ischemic and traumatic injury (1, 2), the peripheral nerve from diabetic damage (3), the kidney from ischemic (4, 5) or toxic insults (6), and the heart from acute ischemia, either permanent (7-9) or with reperfusion (10). Current data suggest that the observed protective effects of EPO depend on an antiapoptotic effect of this cytokine (7, 10). In the brain, EPO also greatly reduces the inflammatory response after ischemiareperfusion (11). It is notable that in several acute models, e.g., brain ischemia, a single dose of EPO that does not increase the Hb concentration nevertheless confers neuroprotection. However, in other in vivo injury models, including cardiac ischemia with reperfusion and diabetic neuropathy, injury develops gradually, and multiple doses of EPO appear superior but also increase the Hb concentration. The possibility that part of the benefit obtained with EPO in these models may depend on the increased oxygen-carrying capacity of the blood cannot be excluded. However, cardiac protection has clearly been demonstrated after only a single dose (8, 10) when evaluated 1-3 days after infarction before any increase i...

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Erythropoietin and hypoxia stimulate erythropoietin receptor and nitric oxide production by endothelial cells

Cited by 262 publications

References 51 publications

Vhl is required for normal pancreatic β cell function and the maintenance of β cell mass with age in mice

Vhl is required for normal pancreatic β cell function and the maintenance of β cell mass with age in mice

Endogenous Erythropoietin Signaling Is Required for Normal Neural Progenitor Cell Proliferation

A nonerythropoietic derivative of erythropoietin protects the myocardium from ischemia–reperfusion injury

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