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LIMITATION OF INFARCT SIZE BY ERYTHROPOIETIN IS ASSOCIATED WITH TRANSLOCATION OF Akt TO THE MITOCHONDRIA AFTER REPERFUSION
Author(s) -
Kobayashi Hironori,
Miura Tetsuji,
Ishida Hideyuki,
Miki Takayuki,
Tanno Masaya,
Yano Toshiyuki,
Sato Takahiro,
Hotta Hiroyuki,
Shimamoto Kazuaki
Publication year - 2008
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/j.1440-1681.2008.04925.x
Subject(s) - erythropoietin , chromosomal translocation , mitochondrion , protein kinase b , medicine , cardiology , endocrinology , chemistry , microbiology and biotechnology , apoptosis , biology , biochemistry , gene
SUMMARY1 The aim of the present study was to determine the critical timing of Akt activation and its interaction with the mitochondrial permeability transition pore (mPTP) in the mechanism of infarct size limitation by erythropoietin (Epo). 2 In an isolated, buffer‐perfused preparation, rabbit hearts were subjected to 30 min ischaemia/2 h reperfusion. Infusion of Epo (1 unit/mL) before ischaemia reduced infarct size from 36.6 ± 2.6% of the risk area to 15.4 ± 3.2%, whereas a 10‐fold higher dose of Epo infused for 65 min commencing 5 min before reperfusion failed to afford significant cardioprotection. The protection afforded by Epo pretreatment was abolished by coinfusion of 5 mmol/L LY294002, a phosphatidylinositol 3‐kinase (PI3‐K) inhibitor. Infusion of Epo induced phosphorylation of Akt, extracellular signal‐regulated kinase, glycogen synthase kinase 3b and p70s6 kinase before ischaemia and tended to enhance reperfusion‐induced phosphorylation of these protein kinases. Erythropoietin increased phospho‐Akt in the mitochondria and induced complex formation of Akt with adenine nucleotide translocase (ANT), a major subunit of mPTP, upon reperfusion. 3 In another series of experiments, cardiomyocytes were isolated from rat hearts and loaded with Rhod‐2 to determine mitochondrial Ca 2+ levels. Increases in mitochondrial Ca 2+ levels following exposure to 1 mmol/L ouabain for 30 min were similar in untreated and Epo‐pretreated cells. However, ouabain‐induced hypercontracture was significantly suppressed from 45.1 ± 1.6 to 39.2 ± 1.9% by Epo. 4 In conclusion, activation of PI3‐K–Akt signalling before ischaemia is crucial for Epo‐induced myocardial protection and this protection may be achieved by complex formation of activated Akt with mPTP components upon reperfusion, leading to elevation of the threshold for opening of mPTP.