scholarly journals Endoplasmic Reticulum Stress in Diabetic Hearts Abolishes Erythropoietin-Induced Myocardial Protection by Impairment of Phospho–Glycogen Synthase Kinase-3β–Mediated Suppression of Mitochondrial Permeability Transition

Diabetes ◽  
2009 ◽  
Vol 58 (12) ◽  
pp. 2863-2872 ◽  
Author(s):  
Takayuki Miki ◽  
Tetsuji Miura ◽  
Hiroyuki Hotta ◽  
Masaya Tanno ◽  
Toshiyuki Yano ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Myocardial Protection ◽  
Mitochondrial Permeability Transition ◽  
Glycogen Synthase ◽  
Permeability Transition ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β ◽  
Mitochondrial Permeability

scholarly journals Phosphorylation of GSK-3β Mediates Intralipid-induced Cardioprotection against Ischemia/Reperfusion Injury

2011 ◽  
Vol 115 (2) ◽  
pp. 242-253 ◽  
Author(s):  
Siamak Rahman ◽  
Jingyuan Li ◽  
Jean Chrisostome Bopassa ◽  
Soban Umar ◽  
Andrea Iorga ◽  
...  
Keyword(s):  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Glycogen Synthase ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Glycogen Synthase Kinase ◽  
Control Group ◽  
Glycogen Synthase Kinase 3Β ◽  
Mitochondrial Permeability

Background Intralipid (Sigma, St. Louis, MO), a brand name for the first safe fat emulsion for human use, has been shown to be cardioprotective. However, the mechanism of this protection is not known. The authors investigated the molecular mechanism(s) of Intralipid-induced cardioprotection against ischemia/reperfusion injury, particularly the role of glycogen synthase kinase-3β (GSK-3β) and mitochondrial permeability transition pore in this protective action. Methods In vivo rat hearts or isolated Langendorff-perfused mouse hearts were subjected to ischemia followed by reperfusion with Intralipid (1% in ex vivo and one bolus of 20% in in vivo) or vehicle. The hemodynamic function, infarct size, threshold for the opening of mitochondrial permeability transition pore, and phosphorylation levels of protein kinase B (Akt)/extracellular signal regulating kinase (ERK)/GSK-3β were measured. Results Administration of Intralipid at the onset of reperfusion resulted in approximately 70% reduction in infarct size in the in vivo rat model. Intralipid also significantly improved functional recovery of isolated Langendorff-perfused mouse hearts as the rate pressure product was increased from 2,999 ± 863 mmHg*beats/min in the control group to 13,676 ± 611 mmHg*beats/min (mean±SEM) and the infarct size was markedly smaller (18.3 ± 2.4% vs. 54.8 ± 2.9% in the control group, P < 0.01). The Intralipid-induced cardioprotection was fully abolished by LY294002, a specific inhibitor of PI3K, but only partially by PD98059, a specific ERK inhibitor. Intralipid also increased the phosphorylation levels of Akt/ERK1/glycogen synthase kinase-3β by eightfold, threefold, and ninefold, respectively. The opening of mitochondrial permeability transition pore was inhibited by Intralipid because calcium retention capacity was higher in the Intralipid group (274.3 ± 8.4 nM/mg vs. 168.6 ± 9.6 nM/mg in the control group). Conclusions Postischemic treatment with Intralipid inhibits the opening of mitochondiral permeability transition pore and protects the heart through glycogen synthase kinase-3β via PI3K/Akt/ERK pathways.

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