Erythropoietin Prevention Trial of Coronary Restenosis and Cardiac Remodeling After ST-Elevated Acute Myocardial Infarction (EPOC-AMI)  - A Pilot, Randomized, Placebo-Controlled Study -

Taniguchi, Nobuyuki; Nakamura, Takeshi; Sawada, Takahisa; Matsubara, Kazuo; Furukawa, Koichi; Hadase, Mitsuyoshi; Nakahara, Yoshifumi; Nakamura, Takashi; Matsubara, Hiroaki

doi:10.1253/circj.cj-10-0267

Cited by 75 publications

(47 citation statements)

References 38 publications

(36 reference statements)

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“…52 In contrast, a low dose of erythropoietin appears to be cardioprotective. 54, 55 Platelet activation by a high-dose of erythropoietin and the existence of an optimal dose for limiting infarct size will explain the dose-dependent discrepancy of erythropoietin-induced cardioprotection. 56-58 Therefore, a large-scale, doubleblinded, placebo-controlled study is being conducted to clarify the effects of a low dose of erythropoietin on cardiac function after 6 months in patients with AMI who received successful PCI in Japan (UMIN000005721).…”

Section: Ischemic Postconditioningmentioning

confidence: 99%

Cardioprotection From Ischemia/Reperfusion Injury

Minamino

2012

Circ J

105

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Section: Ischemic Postconditioningmentioning

confidence: 99%

Cardioprotection From Ischemia/Reperfusion Injury

Minamino

2012

Circ J

105

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“…49,50) GATA-4 has been shown to play a role as a survival factor that can break the vicious cycle of postinfarction heart failure. That EPO-ERK activation stabilizes GATA-4 activity by activating phosphorylation and diminishing ubiquitination of GATA-4 provides a clue into a possible molecular mechanism of the previously reported cardioprotective effects of EPO.…”

Section: Discussionmentioning

confidence: 99%

Erythropoietin Prevents Hypoxia-Induced GATA-4 Ubiquitination <i>via</i> Phosphorylation of Serine 105 of GATA-4

Jun

Shin

Kim

et al. 2013

Biological & Pharmaceutical Bulletin

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Erythropoietin (EPO), an essential hormone for erythropoiesis, can provide protection against myocardial ischemia/reperfusion (I/R) injury and hypoxic apoptosis. GATA-4 is a zinc finger transcription factor, and its activation and post-translational modification are essential components in the transcriptional response to hypoxia. GATA-4 has also been reported to play a role in the cellular mechanisms of EPO-induced myocardial protection against I/R injury. In this study, we aimed to investigate the influence of EPO on GATA-4 protein stability and post-translational modification under hypoxic conditions without reperfusion. EPO induced cell viability under long-term hypoxia. EPO significantly increased phosphorylation of GATA-4 via the extracellular signal-regulated kinase (ERK) signaling pathway and reduced hypoxia-induced GATA-4 ubiquitination, which enhanced GATA-4 stability under hypoxia. ERK activation by over-expression of constitutively active mitogen-activated protein kinase 1 (MEK1) strongly increased GATA-4 phosphorylation and its protein levels and decreased GATA-4 ubiquitination under hypoxia. Despite ERK activation, GATA-4 ubiquitination was not affected under hypoxia in a GATA-4-S105A mutant. Under hypoxic condition without reperfusion, EPO-induced ERK activation was associated with post-translational modification of GATA-4, mediated by enhancement of phosphorylation of GATA-4 at Ser-105. Subsequent attenuation of GATA-4 ubiquitination led to increases in GATA-4 protein stability, which resulted in increased cell viability under hypoxia.

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“…Two small studies showed positive effects. Taniguchi et al 60 studied the effect of low-dose erythropoietin (6000 IU during PCI for acute MI) on in-stent neointimal volume, myocardial infarct size, and LV function. There was no significant difference in absolute infarct size between groups at 4 days or 6 months.…”

Section: Other Older and Newer Pharmacological Approaches Erythropoietinmentioning

confidence: 99%

“…60,61 Large REVEAL study showed no reduction of infarct size 62,63 and several other recent trials were negative for infarct size reduction [64][65][66][67] Glucose-insulin-potassium Recent large IMMEDIATE trial assessed 12 h GIK infusion started out-of-hospital. No decrease in progression to enzymatic evidence of infarction.…”

Section: Erythropoietinmentioning

confidence: 99%

Current State of Clinical Translation of Cardioprotective Agents for Acute Myocardial Infarction

Kloner

2013

Circulation Research

137

112

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Abstract:There is continued interest in the concept of limiting myocardial infarct size with adjunctive agents administered along with reperfusion injury; however, there remains considerable controversy in the literature. The purpose of this article is to review the medical literature on clinical trials performed during the past 3 years that have attempted to reduce myocardial infarct size by administration of adjunctive therapies along with reperfusion therapy. A PubMed-driven literature search revealed a host of clinical trials focusing on the following prominent types of therapies: endogenous conditioning (postconditioning and remote ischemic conditioning); rapid cooling; pharmacological therapy (cyclosporine, abciximab, clopidogrel, tirofiban, erythropoietin, thrombus aspiration, adenosine, glucose-insulin-potassium, statins, antidiabetic agents, FX06, iron chelation, and ranolazine). Although there remains some controversy, quite a few of these studies showed that adjunctive therapy further reduced myocardial infarct size when coupled with reperfusion. Antiplatelet agents are emerging as some of the newest agents that seem to have cardioprotective capabilities. Postconditioning has become a bit more controversial in the clinical literature; remote conditioning, early and rapid cooling, adenosine, and ranolazine are intriguing therapies deserving of larger studies. Certain agents and maneuvers, such as erythropoietin, protein kinase C δ inhibitors, iron chelation, and intra-aortic balloon counterpulsation, perhaps should be retired. The correct adjunctive therapy administered along with reperfusion has the capability of further reducing myocardial injury during ST-segment-elevation myocardial infarction. ( infarct size reducing agents in clinical trials. Some of these disappointing agents included antibodies that prevent white blood cell adhesion to the endothelium; eniporide, a sodium/hydrogen exchange inhibitor; caldaret, an intracellular calcium-handling modulator; nicorandil, a potassium ATP channel opener/vasodilator; glucose-insulin-potassium (GIK); delcasertib (a protein kinase C δ inhibitor); and erythropoietin. 5 However, some agents and maneuvers that were observed to work in experimental models did show promise in clinical trials of MI under the right circumstances: postconditioning; remote conditioning; cyclosporine (maintains the mitochondrial permeability transition pore closed); intravenous adenosine infusions; atrial natriuretic peptide; mild hypothermia induced before reperfusion; supersaturated oxygen therapy and others. [4][5][6][7] The reasons for discrepancies between experimental findings and clinical trials have been reviewed in detail. 6,7 Since these reviews were written there have been a large number of new clinical trials recently published during the past 3 years, on the basis of literature searches through PubMed. These trials cover additional new studies on therapies, such as conditioning, abciximab, clopidogrel, erythropoietin, hypothermia, thrombectomy, intracoronary adenosine...

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Erythropoietin Prevention Trial of Coronary Restenosis and Cardiac Remodeling After ST-Elevated Acute Myocardial Infarction (EPOC-AMI) - A Pilot, Randomized, Placebo-Controlled Study -

Cited by 75 publications

References 38 publications

Cardioprotection From Ischemia/Reperfusion Injury

Cardioprotection From Ischemia/Reperfusion Injury

Erythropoietin Prevents Hypoxia-Induced GATA-4 Ubiquitination <i>via</i> Phosphorylation of Serine 105 of GATA-4

Current State of Clinical Translation of Cardioprotective Agents for Acute Myocardial Infarction

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