Repeated Low-dose of Erythropoietin is Associated with Improved Left Ventricular Function in Rat Acute Myocardial Infarction Model

Ben‐Dor, Itsik; Hardy, Britta; Fuchs, Shmuel; Kaganovsky, Ella; Kadmon, Ehud; Sagie, Alex; Coleman, Raymond; Mansur, Mali; Politi, Boaz; Fraser, Abigail; Harell, Daniella; Okon, Elimelech; Battler, Alexander; Haim, Moti

doi:10.1007/s10557-007-6049-8

Cited by 14 publications

(9 citation statements)

References 41 publications

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“…This is most probably due to the increased hematocrit, affecting rheological blood properties, nutritive perfusion and metabolic functions of injured tissues 3. 11 In the present study, we observed a significantly increased hematocrit at 2 and 5 weeks after daily 500 U/kg EPO administration. Although we observed a massive acceleration of bone regeneration, the increased hematocrit may have affected the healing process.…”

Section: Discussionsupporting

confidence: 52%

Low dose erythropoietin stimulates bone healing in mice

Garcia

Speidel

Scheuer

et al. 2010

Journal Orthopaedic Research

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Beyond its classical role in regulation of erythropoiesis, erythropoietin (EPO) has been shown to exert protective and regenerative actions in a variety of non-hematopoietic tissues. However, little is known about potential actions in bone regeneration. To analyze fracture healing in mice, a femoral 0.25 mm osteotomy gap was stabilized with a pin-clip technique. Animals were treated with 500 U EPO/kg bw per day or with vehicle only. After 2 and 5 weeks, fracture healing was analyzed biomechanically, radiologically and histologically. Expression of PCNA and NFB was examined by Western blot analysis. Vascularization was analyzed by immunohistochemical staining of PECAM-1. Circulating endothelial progenitor cells were measured by flow-cytometry. Herein, we demonstrate that EPOtreatment significantly accelerates bone healing in mice. This is indicated by a significantly greater biomechanical stiffness and a higher radiological density of the periosteal callus at 2 and 5 weeks after fracture and stabilization. Histological analysis demonstrated significantly more bone and less cartilage and fibrous tissue in the periosteal callus. Endosteal vascularization was significantly increased in EPO-treated animals when compared to controls. The number of circulating endothelial progenitor cells was significantly greater in EPO-treated animals. The herein shown acceleration of healing by EPO may represent a promising novel treatment strategy for fractures with delayed healing and non-union formation. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J. Orthop. Res. 29: 165-172, 2011 Keywords: mouse; erythropoietin; fracture healing; bone healing; bone regeneration Beyond its role in the regulation of red blood cell proliferation, the glycoprotein erythropoietin (EPO) has been shown to exert protective and regenerative actions in a variety of non-hematopoietic tissues. In a previous study we could show that daily application of 5,000 U/kg EPO for 5 days (high-dose, short-time) enhances early endochondral ossification and mechanical strength in a closed femoral fracture model in mice. 2 However, the initial effect of short-time and high-dose application of EPO was found vanished after 5 weeks, most probably because of the good healing response of closed fractures in mice and the limitation of EPO administration to only 5 days post fracture. In the present study we analyzed, whether EPO is capable of accelerating healing of fractures with small segmental defects in mice. Because several studies have shown that high EPO doses of up to 5,000 U/kg/day are not necessary to achieve tissue protection and that this high doses can be associated with adverse effects, 3 we have studied low-dose treatment with only 500 U/kg/day EPO. Further, because the EPO-receptor has been shown to be expressed within the periosteal callus over several weeks during fracture healing, 2 EPO was given in the present study as a long term treatment over a period of 5 weeks. MATERIALS AND METHODS AnimalsA total of 52 CD-1 m...

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Section: Discussionsupporting

confidence: 52%

Low dose erythropoietin stimulates bone healing in mice

Garcia

Speidel

Scheuer

et al. 2010

Journal Orthopaedic Research

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“…In addition, EH‐201 acted as an EPO/EPOR enhancer, which may help to increase EPOR sensitivity. Low‐dose EPO treatment has been shown to be beneficial in animal models of myocardial infarction (Ben‐Dor et al ., ) and when applied clinically (Minamino et al ., ). Additionally, the endogenous EPO/EPOR system in non‐haematopoietic cells has been found to exert cardioprotective effects (Asaumi et al ., ).…”

Section: Discussionmentioning

confidence: 99%

Activation of mitochondrial function and Hb expression in non‐haematopoietic cells by an EPO inducer ameliorates ischaemic diseases in mice

Hsu¹,

Horng²,

Peng³

et al. 2013

British J Pharmacology

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BACKGROUND AND PURPOSEMany organs suffer from ischaemic injuries that reduce their ability to generate sufficient energy, which is required for functional maintenance and repair. Erythropoietin (EPO) ameliorates ischaemic injuries by pleiotropic effects. The aim of this study was to investigate the effect and mechanism of a small molecule EH-201, and found it as a potent EPO inducer and its effect in non-haematopoietic cells for therapeutic potential in ischemic disorders. EXPERIMENTAL APPROACHMice kidney slices, primary hepatocytes, primary cardiomyocytes and C2C12 myoblasts were treated with EH-201. The effects of this treatment on EPO, Hb expression and mitochondrial biogenesis were analysed. In vivo, doxorubicin-induced cardiomyopathic mice were treated with EH-201. The mice were subjected to an endurance test, electrocardiography and echocardiography, and a histological examination of the isolated hearts was performed. EH-201 was also administered to cisplatin-induced nephropathic mice. KEY RESULTSIn non-haematopoietic cells, EH-201 was potent at inducing EPO. EH-201 also stimulated mitochondrial biogenesis and enhanced the expression of Hb by a mechanism dependent on EPO-mediated signalling. In mechanistic studies, using EPO and EPO receptor-neutralizing antibodies, we confirmed that EH-201 enhances EPO-EPOR autocrine activity. EH-201 robustly increased the endurance performance activity of healthy and cardiomyopathic mice during hypoxic stress, enhanced myocardial mitochondrial biogenesis and Hb expression, and also improved cardiac function. EH-201 ameliorated anaemia and renal dysfunction in nephropathic mice. CONCLUSIONS AND IMPLICATIONSThe enhancement and recovery of cellular functions through the stimulation of mitochondrial activity and Hb production in non-haematopoietic cells by an inducer of endogenous EPO has potential as a therapeutic strategy for ischaemic diseases. AbbreviationsBUN, blood urea nitrogen; Dox, doxorubicin; EH-201, 2,3,5,4′-tetrahydroxystilbene-2-o-b-d-glucoside; EPO, erythropoietin; EPOR, EPO receptor; Hif, hypoxia-inducible factor; mtDNA, mitochondrial DNA; PGC-1a, PPAR co-activator 1a; Sirt1, sirtuin BJP British Journal of Pharmacology

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“…In cell culture and animal studies, EPO is cytoprotective during elevated glucose (Chong et al, 2007c) and can block apoptotic DNA degradation during elevated glucose similar to other models of oxidative stress in cardiac and vascular cell models (Avasarala & Konduru, 2005;Chong et al, 2002bChong et al, , 2003aMoon et al, 2006). EPO can at times enhance tissue function (Ben-Dor et al, 2007) and is closely related to the maintenance of mitochondrial membrane potential (ΔΨ m ) (Li et al, 2004a). Loss of ΔΨ m through the opening of the mitochondrial permeability transition pore represents a significant determinant for cell injury and the subsequent induction of apoptosis (Leuner et al, 2007;.…”

Section: The Wnt Pathway and Metabolic Diseasementioning

confidence: 99%

The Wnt signaling pathway: Aging gracefully as a protectionist?

Maiese

Chong

et al. 2008

Pharmacology & Therapeutics

151

174

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No longer considered to be exclusive to cellular developmental pathways, the Wnt family of secreted cysteine-rich glycosylated proteins has emerged as versatile targets for a variety of conditions that involve cardiovascular disease, aging, cancer, diabetes, neurodegeneration, and inflammation. In particular, modulation of Wnt signaling may fill a critical void for the treatment of disorders that impact upon both cellular survival and cellular longevity. Yet, in some scenarios, Wnt signaling can become the catalyst for disease development or promote cell senescence that can compromise clinical utility. This double edge sword in regards to the role of Wnt and its signaling pathways highlights the critical need to further elucidate the cellular mechanisms governed by Wnt in conjunction with the development of robust pharmacological ligands that may open new avenues for disease treatment. Here we discuss the influence of the Wnt pathway during cell survival, metabolism, and aging in order for one to gain a greater insight for the novel role of Wnt signaling as well as exemplify its unique cellular pathways that influence both normal physiology and disease.

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Repeated Low-dose of Erythropoietin is Associated with Improved Left Ventricular Function in Rat Acute Myocardial Infarction Model

Abstract: Repeated low doses of Epo after MI improved LV function, but the role of Epo on remodeling is not clear. It did not reduce left ventricular indices, but reduces fibrosis and apoptosis. High Epo doses reduced LV function and aggravated remodeling.

Cited by 14 publications

References 41 publications

Low dose erythropoietin stimulates bone healing in mice

Low dose erythropoietin stimulates bone healing in mice

Activation of mitochondrial function and Hb expression in non‐haematopoietic cells by an EPO inducer ameliorates ischaemic diseases in mice

The Wnt signaling pathway: Aging gracefully as a protectionist?

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