Asialoerythropoietin Has Strong Renoprotective Effects Against Ischemia-Reperfusion Injury in a Murine Model

Okada, Toshie; Sawada, Tokihiko; Kubota, Keiichi

doi:10.1097/01.tp.0000277672.02783.33

Cited by 42 publications

(33 citation statements)

References 30 publications

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“…For example, both asialoEPO and a small peptide mimic of EPO (pyroglutamate helix B surface peptide [pHBSP] [62]) have plasma half-lives of only ~2 min. Yet both are highly effective in preventing injury in a wide range of neurological and other acute injuries after only a single parenteral dose (32,(64)(65)(66).…”

Section: Development Of Tissue-protective Receptor-specific Ligandsmentioning

confidence: 99%

The Receptor That Tames the Innate Immune Response

Brines

Cerami

2011

Mol Med

115

101

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Section: Development Of Tissue-protective Receptor-specific Ligandsmentioning

confidence: 99%

The Receptor That Tames the Innate Immune Response

Brines

Cerami

2011

Mol Med

115

101

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“…This concept was further validated in other tissues, including kidneys. 12 Administration of asialoEPO also protected against ischemia reperfusion injury in the heart, possibly through mechanisms involving inhibition of apoptosis. 13 In addition, we recently demonstrated that asialoEPO attenuates nephrectomy induced left ventricular remodeling and dysfunction without increasing hemoglobin levels.…”

mentioning

confidence: 99%

Asialoerythropoietin, a Nonerythropoietic Derivative of Erythropoietin, Displays Broad Anti-Heart Failure Activity

Takahashi

Takemura²,

Kanamori³

et al. 2012

Circ: Heart Failure

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Background-We investigated the effects of asialoerythropoietin (asialoEPO), a nonerythrogenic erythropoietin derivative, on 3 murine models of heart failure with different etiologies. Methods and Results-Doxorubicin (15 mg/kg) induced heart failure within 2 weeks (toxic cardiomyopathy). Treatment with asialoEPO (6.9 g/kg) for 2 weeks thereafter attenuated the associated left ventricular dysfunction and dilatation. In addition, the asialoEPO-treated heart showed less myocardial fibrosis, inflammation, and oxidative damage, and diminished atrophic cardiomyocyte degeneration, which was accompanied by restored expression of GATA-4 and sarcomeric proteins. Mice with large 6-week-old myocardial infarctions exhibited marked left ventricular dysfunction with adverse remodeling (ischemic cardiomyopathy). AsialoEPO treatment for 4 weeks significantly mitigated progression of the dysfunction and remodeling and reduced myocardial fibrosis, inflammation, and oxidative damage. Finally, 25-week-old ␦-sarcoglycan-deficient mice (genetic cardiomyopathy) were treated with asialoEPO for 5 weeks. AsialoEPO mitigated the progressive cardiac remodeling and dysfunction through cardiomyocyte hypertrophy, and upregulated expression of GATA-4 and sarcomeric proteins. AsialoEPO appears to act by altering the activity of the downstream erythropoietin receptor signals extracellular signal-regulated protein kinase, Akt, signal transducer, and activator of transcription 3 and 5 in a model-specific manner. Conclusions-The findings suggest that asialoEPO exerts broad cardioprotective effects through distinct mechanisms depending on the model, which are independent of the erythrogenic action. This compound may be promising for the treatment of heart failure of various etiologies. (Circ Heart Fail. 2012;5:274-285.)Key Words: cardiomyopathy Ⅲ erythropoietin Ⅲ heart failure E rythropoietin (EPO) is a hypoxia-induced hormone that is essential for normal erythropoiesis and is used widely in patients with anemia. Notably, however, the EPO receptor is also expressed on cells within the cardiovascular system, including cardiomyocytes and endothelial cells, suggesting EPO exerts cardiovascular effects beyond hematopoiesis. [1][2][3] For example, recombinant human EPO exerts cardioprotective effects in hearts subjected to acute myocardial infarction or ischemia-reperfusion injury, that is, EPO administration prior to or during myocardial ischemia significantly enhances functional recovery after reperfusion. 4,5 In addition, EPO administered during the chronic stage of myocardial infarction acts via a different mechanism to mitigate the cardiac dysfunction and remodeling caused by the old myocardial infarction. 6 EPO also appears to exert a protective effect against heart disease of nonischemic origin, for example doxorubicin cardiomyopathy. 7 Taken together, these findings suggest that EPO acts as a tissue-protective cytokine in heart disease, and that it exerts different effects on diseased hearts through various mechanisms, depending on the disease typ...

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“…46 In fact, the action of Epo does not seem to be limited to controlling proliferation and differentiation of erythroid cells. It overcomes the effect on the hematopoietic system [47][48][49] and functional receptors for Epo have been found in both nonerythroid blood cell lines and a variety of nonhematopoietic cells, suggesting new roles in nonhematopoietic tissues. These include brain (astrocytes and neurons, both provided with specific Epo-R), cardiovascular system (cardiomyocytes, endothelium, and vascular smooth muscle), spinal cord, reproductive organs, skeletal muscle, retina, gastrointestinal tract (gut and pancreas), and lung.…”

Section: Extra-erythropoietic Actions Of Epo: Opening New Frontiersmentioning

confidence: 98%

Emerging technologies in the delivery of erythropoietin for therapeutics

Murua

Orive

Hernández

et al. 2011

Medicinal Research Reviews

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Deciphering the function of proteins and their roles in signaling pathways is one of the main goals of biomedical research, especially from the perspective of uncovering pathways that may ultimately be exploited for therapeutic benefit. Over the last half century, a greatly expanded understanding of the biology of the glycoprotein hormone erythropoietin (Epo) has emerged from regulator of the circulating erythrocyte mass to a widely used therapeutic agent. Originally viewed as the renal hormone responsible for erythropoiesis, recent in vivo studies in animal models and clinical trials demonstrate that many other tissues locally produce Epo independent of its effects on red blood cell mass. Thus, not only its hematopoietic activity but also the recently discovered nonerythropoietic actions in addition to new drug delivery systems are being thoroughly investigated in order to fulfill the specific Epo release requirements for each therapeutic approach. The present review focuses on updating the information previously provided by similar reviews and recent experimental approaches are presented to describe the advances in Epo drug delivery achieved in the last few years and future perspectives.

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Asialoerythropoietin Has Strong Renoprotective Effects Against Ischemia-Reperfusion Injury in a Murine Model

Abstract: EPO and asialoEPO attenuated renal dysfunction caused by I/R in mouse kidney at the same level, but only asialoEPO improved survival.

Cited by 42 publications

References 30 publications

The Receptor That Tames the Innate Immune Response

The Receptor That Tames the Innate Immune Response

Asialoerythropoietin, a Nonerythropoietic Derivative of Erythropoietin, Displays Broad Anti-Heart Failure Activity

Emerging technologies in the delivery of erythropoietin for therapeutics

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