TY - JOUR
T1 - Effect of pressure overload on cardioprotection of mitochondrial K ATP channels and GSK-3β
T2 - Interaction with the MPT pore
AU - Mozaffari, Mahmood S.
AU - Schaffer, Stephen W.
N1 - Funding Information:
Acknowledgments:We thank Champa Patel and JunYao Liu for their technical assistance.This study was supported by grants from the NIH (HL-63723) and the American Heart Association, Southeast Affiliate (0755627B).
PY - 2008/5
Y1 - 2008/5
N2 - Background: The mitochondrial permeability transition (MPT) pore may serve as the end-effector of cardioprotective mechanisms, namely the mitochondrial KATP channels and glycogen synthase kinase-3β (GSK-3β). We recently showed that augmented MPT pore induction contributes to pressure overload-induced exacerbation of infarct size. This study tests the hypotheses that (i) elevation in perfusion pressure attenuates cardioprotection associated with activation of mitochondrial KATP channels or inhibition of GSK-3β and (ii) perfusion pressure modulates the regulation of the MPT pore by mitochondrial KATP channels and/or GSK-3β. Methods: Langendorff-perfused hearts were subjected to a regional ischemia-reperfusion insult at a perfusion pressure of either 80 or 160 cm H2O. The perfusion medium contained no drug, diazoxide (80 μmol/l; mitochondrial KATP channel opener), lithium chloride (LiCl, 1 mmol/l; nonselective inhibitor of GSK-3β), SB-216763 (3 μmol/l; selective inhibitor of GSK-3β), cyclosporine A (0.2 μmol/l; inhibitor of MPT pore induction), glibenclamide (50 μmol/l; inhibitor of KATP channels), and the combination of cyclosporine A and glibenclamide or the combination of glibenclamide and LiCl. Results: The increase in perfusion pressure in the absence of a drug caused larger infarcts, an effect associated with poorer recovery of function following ischemia reperfusion. Treatment with either diazoxide or cyclosporine A reduced infarct size at both perfusion pressures but in contrast to diazoxide, cyclosporine A was more protective at the higher pressure. On the other hand, LiCl and SB-216763 reduced infarct size at both pressures, with the effect more marked at the higher perfusion pressure. Glibenclamide did not affect infarct size but eliminated the cardioprotective effect of cyclosporine A while having no effect on LiCl-induced cardioprotection. Conclusion: Perfusion pressure primarily affects GSK-3β-mediated regulation of MPT pore formation in the ischemic reperfused heart.
AB - Background: The mitochondrial permeability transition (MPT) pore may serve as the end-effector of cardioprotective mechanisms, namely the mitochondrial KATP channels and glycogen synthase kinase-3β (GSK-3β). We recently showed that augmented MPT pore induction contributes to pressure overload-induced exacerbation of infarct size. This study tests the hypotheses that (i) elevation in perfusion pressure attenuates cardioprotection associated with activation of mitochondrial KATP channels or inhibition of GSK-3β and (ii) perfusion pressure modulates the regulation of the MPT pore by mitochondrial KATP channels and/or GSK-3β. Methods: Langendorff-perfused hearts were subjected to a regional ischemia-reperfusion insult at a perfusion pressure of either 80 or 160 cm H2O. The perfusion medium contained no drug, diazoxide (80 μmol/l; mitochondrial KATP channel opener), lithium chloride (LiCl, 1 mmol/l; nonselective inhibitor of GSK-3β), SB-216763 (3 μmol/l; selective inhibitor of GSK-3β), cyclosporine A (0.2 μmol/l; inhibitor of MPT pore induction), glibenclamide (50 μmol/l; inhibitor of KATP channels), and the combination of cyclosporine A and glibenclamide or the combination of glibenclamide and LiCl. Results: The increase in perfusion pressure in the absence of a drug caused larger infarcts, an effect associated with poorer recovery of function following ischemia reperfusion. Treatment with either diazoxide or cyclosporine A reduced infarct size at both perfusion pressures but in contrast to diazoxide, cyclosporine A was more protective at the higher pressure. On the other hand, LiCl and SB-216763 reduced infarct size at both pressures, with the effect more marked at the higher perfusion pressure. Glibenclamide did not affect infarct size but eliminated the cardioprotective effect of cyclosporine A while having no effect on LiCl-induced cardioprotection. Conclusion: Perfusion pressure primarily affects GSK-3β-mediated regulation of MPT pore formation in the ischemic reperfused heart.
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U2 - 10.1038/ajh.2008.25
DO - 10.1038/ajh.2008.25
M3 - Article
C2 - 18437149
AN - SCOPUS:42549138502
SN - 0895-7061
VL - 21
SP - 570
EP - 575
JO - American journal of hypertension
JF - American journal of hypertension
IS - 5
ER -