Erythropoietin affords additional cardioprotection to preconditioned hearts by enhanced phosphorylation of glycogen synthase kinase-3 beta.

Abstract

The aim of this study was to determine whether erythropoietin (EPO) affords additional cardioprotection to the preconditioned myocardium by enhanced phosphorylation of Akt, STAT3, or glycogen synthase kinase-3beta (GSK-3 beta). Preconditioning (PC) with 5-min ischemia/5-min reperfusion and EPO (5,000 U/kg iv) reduced infarct size (as % of area at risk, %IS/AR) after 20-min ischemia in rat hearts in situ from 56.5 +/- 1.8% to 25.2 +/- 2.1% and to 36.2 +/- 2.8%, respectively. PC-induced protection was significantly inhibited by a protein kinase C inhibitor, chelerythrine (5 mg/kg), and slightly blunted by a phosphatidylinositol-3-kinase inhibitor, wortmannin (15 microg/kg). The opposite pattern of inhibition was observed for EPO-induced protection. The combination of PC and EPO further reduced %IS/AR to 8.9 +/- 1.9%, and this protection was inhibited by chelerythrine and wortmannin. The additive effects of PC and EPO on infarct size were mirrored by their effects on the level of phosphorylated GSK-3 beta at 5 min after reperfusion but not their effects on the level of phospho-Akt or phospho-STAT3. To mimic phosphorylation-induced inhibition of GSK-3 beta activity, SB-216763 (SB), a GSK-3 beta inhibitor, was administered before ischemia or 5 min before reperfusion. Infarct size was significantly reduced by preischemic injection (%IS/AR = 40.4 +/- 2.2% by 0.6 mg/kg SB and 34.0 +/- 1.8% by 1.2 mg/kg SB) and also by prereperfusion injection (%IS/AR = 32.0 +/- 2.0% by 1.2 mg/kg SB). These results suggest that EPO and PC afford additive infarct size-limiting effects by additive phosphorylation of GSK-3beta at the time of reperfusion by Akt-dependent and -independent mechanisms.

• Authors: Masahiro Nishihara, Tetsuji Miura, Takayuki Miki, Jun Sakamoto, Masaya Tanno, Hironori Kobayashi, Yoshihiro Ikeda, Katsuhiko Ohori, Akari Takahashi, Kazuaki Shimamoto
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 291 Issue 2 Pg. H748-55 (Aug 2006) ISSN: 0363-6135 [Print] United States
• PMID: 16565311 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cardiotonic Agents
• STAT3 Transcription Factor
• Erythropoietin
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, rat
• Proto-Oncogene Proteins c-akt
• Glycogen Synthase Kinase 3

Topics

• Animals
• Blotting, Western
• Cardiotonic Agents
• Erythropoietin (pharmacology)
• Glycogen Synthase Kinase 3 (antagonists & inhibitors, biosynthesis)
• Glycogen Synthase Kinase 3 beta
• Hemodynamics (physiology)
• Ischemic Preconditioning, Myocardial
• Male
• Myocardial Infarction (pathology)
• Myocardium (pathology)
• Organ Size (physiology)
• Phosphorylation
• Proto-Oncogene Proteins c-akt (biosynthesis, genetics)
• Rats
• Rats, Sprague-Dawley
• STAT3 Transcription Factor (biosynthesis)