title: Erythropoietin protects myocardium against ischemia-reperfusion injury under moderate hyperglycemia.
abstract: Erythropoietin (EPO), an essential hormone for erythropoiesis, provides protection against myocardial ischemia/reperfusion (I/R) injury. Hyperglycemia during acute myocardial infarction aggravates organ damage and attenuates the efficacies of various protective measures. This study aimed to investigate the protective role of EPO against myocardial I/R injury under a clinically relevant moderate hyperglycemic condition and its associated mechanisms. Eighty-two Sprague-Dawley rats were randomly assigned to six groups: normoglycemia-Sham, normoglycemia-I/R-control-saline (IRC), normoglycemia-I/R-EPO (IRE), hyperglycemia-Sham, hyperglycemia-IRC, and hyperglycemia-IRE. The rats received 1.2 g/kg dextrose or same volume of normal saline depending on the group. I/R was induced by a 30 min period of ischemia followed by reperfusion for 4 h. For 1 h before I/R injury, intravenous 4000 IU/kg of EPO was administered. EPO pretreatment significantly reduced the number of apoptotic cells and the infarct size compared with those of the control groups. EPO increased GATA-4 phosphorylation and acetylation against I/R in hyperglycemic myocardium. It also enhanced ERK induced GATA-4 post-translational modifications such as increased GATA-4 phosphorylation and acetylation, and decreased GATA-4 ubiquitination following hypoxia-reoxygenation in H9c2 cells in hyperglycemic medium. Increased GATA-4 stability by EPO diminished I/R-related down-regulation of Bcl-2 and reduction of caspase-3 activities in hyperglycemic myocardium. In conclusion, EPO pretreatment before I/R injury conveyed significant myocardial protection under moderate hyperglycemic condition through mechanisms involved in reduction of caspase-3 activity and up-regulation of Bcl-2 in association with enhanced ERK-induced GATA-4 stability.
authors.affiliation: Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Ji Hae
authors.initials: JH
authors.lastname: Jun
authors.affiliation: Department of Anesthesiology and Pain Medicine, National Health Insurance Corporation Ilsan Hospital, Goyang, Republic of Korea.
authors.forename: Na-Hyung
authors.initials: NH
authors.lastname: Jun
authors.affiliation: Department of Anesthesiology and Pain Medicine, Yonsei Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jae-Kwang
authors.initials: JK
authors.lastname: Shim
authors.affiliation: Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Shin
authors.affiliation: Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea; Department of Anesthesiology and Pain Medicine, Yonsei Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address: ylkwak@yuhs.ac.
authors.forename: Young-Lan
authors.initials: YL
authors.lastname: Kwak
mesh_terms: D000107:Acetylation; D000818:Animals; D017209:Apoptosis; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D004921:Erythropoietin / Q000008:administration & dosage* / Q000378:metabolism; D050991:GATA4 Transcription Factor / Q000378:metabolism; D006943:Hyperglycemia / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D054875:Ubiquitination
chemical_list: D002316:Cardiotonic Agents; D050991:GATA4 Transcription Factor; C084365:Gata4 protein, rat; D019253:Proto-Oncogene Proteins c-bcl-2; C000599851:erythropoietin, rat; D004921:Erythropoietin; C505410:Casp3 protein, rat; D053148:Caspase 3
keywords: Bcl-2; Cardioprotection; Caspase-3; Erythropoietin; GATA binding protein-4; Hyperglycemia