Cytoprotective regulation of the mitochondrial permeability transition pore is impaired in type 2 diabetic Goto-Kakizaki rat hearts.
Our recent studies indicated that up-regulation of calcineurin activity and unfolded protein responses (UPRs) disrupt cytoprotective Akt- and ERK-signaling in OLETF, a model of obese type 2 diabetes (T2DM). To determine whether the mechanisms can be generalized, we used Goto-Kakizaki rats (GK), a model of non-obese T2DM, in this study. Infarct sizes after 20-min ischemia/2-h reperfusion were similar in GK and non-diabetic controls, Wistar rats (Wistar). However, erythropoietin (EPO) limited infarct size in Wistar (64.0±5.3% vs. 45.7±4.4%, p<0.05) but not in GK (56.2±2.2% vs. 52.6±2.3%). Levels of calcineurin activity and EPO-induced phosphorylation of Akt and ERK were similar in GK and Wistar, though cytosolic HSP70 level was 50% lower and mitochondrial HSP60 level was 60% higher in GK. EPO preserved mitochondrial calcium retention capacity (CRC), an index of the threshold for opening of the mitochondrial permeability transition pore (mPTP), after ischemia/reperfusion in Wistar but not in GK. Interaction of cyclophilin D (CypD) with mitochondrial inorganic phosphate carrier (PiC), which sensitizes the mPTP, was enhanced in GK. There was a negative exponential relationship between CypD-PiC interaction and CRC upon reperfusion, indicating that increase in CRC by reduction of CypD-PiC interaction is smaller when CypD-PiC interaction level is at a higher range. A chemical chaperone, 4-phenylbutyric acid, attenuated the changes in HSPs and CypD-PiC interaction and restored responses of CRC and infarct size to EPO in GK. These results suggest that cytoprotective regulation of the mPTP is impaired in GK by enhanced CypD-PiC interaction in which UPRs are involved.
Division of Cardiology, Second Department of Internal Medicine, Sapporo Medical University, School of Medicine, Sapporo, Japan.
Takahito
T
Itoh
Hidemichi
H
Kouzu
Takayuki
T
Miki
Masaya
M
Tanno
Atsushi
A
Kuno
Tatsuya
T
Sato
Daisuke
D
Sunaga
Hiromichi
H
Murase
Tetsuji
T
Miura
D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D066298:In Vitro Techniques; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects
D002316:Cardiotonic Agents; D000081406:Peptidyl-Prolyl Isomerase F; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D004921:Erythropoietin; D019703:Calcineurin; D021983:Cyclophilins; D002118:Calcium