Erythropoietin Is a Novel Vascular Protectant Through Activation of Akt1 and Mitochondrial Modulation of Cysteine Proteases

Chong, Zhao Zhong; Kang, Jing‐Qiong; Maiese, Kenneth

doi:10.1161/01.cir.0000039103.58920.1f

Cited by 350 publications

(451 citation statements)

References 22 publications

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“…48 Therefore, alternate strategies have been suggested to develop derivations of EPO to reduce erythropoietic activity and potential toxicity; however, sometimes these preparations yield no efficacy against specific disorders 4,22 and can lead to the loss of desirable effects of EPO, including its ability to promote angiogenesis, which is critical for cytoprotection. 3,6,14 In addition to the attempts to reduce potential toxicity during EPO administration, future strategies also must seek to optimize the timing of EPO administration. Experimental in vitro and in vivo studies indicate that the greatest cell survival is achieved with administration closest to the period of an acute toxic insult, suggesting that protection by EPO most likely coincides with the inhibition of early apoptotic cellular pathways that can involve mitochondrial dysfunction and caspase activation.…”

Section: Future Of Epo In Clinical Medicinementioning

confidence: 99%

New Avenues of Exploration for Erythropoietin

Maiese

Chong

2005

JAMA

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495

501

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Section: Future Of Epo In Clinical Medicinementioning

confidence: 99%

New Avenues of Exploration for Erythropoietin

Maiese

Chong

2005

JAMA

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495

501

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“…Genomic DNA fragmentation was determined by the terminal deoxynucleotidyl transferase nick end labeling (TUNEL) assay [17,22]. Briefly, SH-SY5Y cells were fixed in 4% paraformaldehyde/0.2% picric acid/0.05% glutaraldehyde and the 3'-hydroxy ends of cut DNA were labeled with biotinylated dUTP using the enzyme terminal deoxytransferase (Promega, Madison, WI) followed by streptavidin-peroxidase and visualized with 3,3'-diaminobenzidine (Vector Laboratories, Burlingame, CA).…”

Section: Assessment Of Dna Fragmentationmentioning

confidence: 99%

Cellular demise and inflammatory microglial activation during β-amyloid toxicity are governed by Wnt1 and canonical signaling pathways

Chong

Maiese

2007

Cellular Signalling

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164

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Initially described as a modulator of embryogenesis for a number of organ systems, Wnt1 has recently been linked to the development of several neurodegenerative disorders, none being of greater significance than Alzheimer's disease. We therefore examined the ability of Wnt1 to oversee vital pathways responsible for cell survival during β-amyloid (Aβ 1-42 )exposure. Here we show that Wnt1 is critical for protection in the SH-SY5Y neuronal cell line against genomic DNA degradation, membrane phosphatidylserine (PS) exposure, and microglial activation, since these neuroprotective attributes of Wnt1 are lost during gene silencing of Wnt1 protein expression. Intimately tied to Wnt1 protection is the presence and activation of Akt1. Pharmacological inhibition of the PI 3-K pathway or gene silencing of Akt1 expression can abrogate the protective capacity of Wnt1. Closely aligned with Wnt1 and Akt1 are the integrated canonical pathways of synthase kinase-3β (GSK-3β) and β-catenin. Through Akt1 dependent pathways, Wnt1 phosphorylates GSK-3β and maintains β-catenin integrity to insure its translocation from the cytoplasm to the nucleus to block apoptosis. Our work outlines a highly novel role for Wnt1 and its integration with Akt1, GSK-3β, and β-catenin to foster neuronal cell survival and repress inflammatory microglial activation that can identify new avenues of therapy against neurodegenerative disorders.

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“…EPO has been shown in vitro to antagonize the apoptosis of endothelial cells subjected to ischemic stressors. 69 EPO thus plays a role in maintaining the integrity of the microvasculature. Additionally, EPO has also been shown to stimulate mitogenesis and support angiogenesis, both functioning to improve tissue oxygenation.…”

Section: Epo Signaling In Nervous System Cellsmentioning

confidence: 99%

Erythropoietin as an antiapoptotic, tissue-protective cytokine

Ghezzi

Brines²

2004

Cell Death Differ

307

238

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Erythropoietin (EPO) increases the number of circulating erythrocytes primarily by preventing apoptosis of erythroid progenitors. In addition to this proerythroid action, results of recent studies show that systemically administered EPO is protective in vivo, in several animal models of neuronal injury. In vitro, EPO prevents neuronal apoptosis induced by a variety of stimuli. This review summarizes the neuroprotective actions of EPO and discusses the underlying mechanisms in terms of signal transduction pathways involved. The understanding of these mechanisms will help differentiate the neuroprotective actions of EPO from its role in the bone marrow.

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Erythropoietin Is a Novel Vascular Protectant Through Activation of Akt1 and Mitochondrial Modulation of Cysteine Proteases

Abstract: The present work serves to illustrate that EPO can offer novel cytoprotection during ischemic vascular injury through direct modulation of Akt1 phosphorylation, mitochondrial membrane potential, and cysteine protease activity.

Cited by 350 publications

References 22 publications

New Avenues of Exploration for Erythropoietin

New Avenues of Exploration for Erythropoietin

Cellular demise and inflammatory microglial activation during β-amyloid toxicity are governed by Wnt1 and canonical signaling pathways

Erythropoietin as an antiapoptotic, tissue-protective cytokine

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