Effect of pressure overload on cardioprotection of mitochondrial KATP channels and GSK-3β interaction with the MPT pore
Effect of pressure overload on cardioprotection of mitochondrial KATP channels and GSK-3β interaction with the MPT pore
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DOI：
10.1038/ajh.2008.25
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发表时间：
2008-05-01
影响因子：
3.2
通讯作者：
Schaffer, Stephen W.
中科院分区：
文献类型：
--
作者：
Mozaffari, Mahmood S.;Schaffer, Stephen W.
线粒体通透性转移（MPT）孔可能作为心脏保护机制的末端执行器，即线粒体K-ATP通道和糖原合成酶激酶-3 β (GSK-3 β)。我们最近发现，MPT孔诱导的增强有助于压力过载引起的梗死面积加剧。本研究验证了以下假设：(i)灌注压力升高减弱与线粒体K-ATP通道激活或GSK-3 β抑制相关的心脏保护作用；（ii）灌注压力通过线粒体K-ATP通道和/或GSK-3 β调节MPT孔的调节。方法在80或160 cm H -2的灌注压力下，对slangendorff灌注心脏进行局部缺血再灌注损伤。灌注介质中不含药物、二氮氧化物(80 μ mol/l，线粒体K-ATP通道openel氯化锂（LiCl, 1 mmol/l， GSK-3 β非选择性抑制剂）、sb216763 （3 μ mol/l， GSK-3 β选择性抑制剂）、环孢素A （0.2 μ mol/l， MPT孔诱导抑制剂）、格列本脲（50 μ mol/l， K-ATP通道抑制剂）、环孢素A与格列本脲联用或格列本脲与LiCl联用。结果在没有药物的情况下，灌注压力的增加导致更大的梗死，这种影响与缺血再灌注后功能恢复较差有关。在两种灌注压力下，用二氮氧化合物或环孢素A治疗均可减少梗死面积，但与二氮氧化合物相比，环孢素A在较高的灌注压力下更具保护作用。另一方面，LiCl和SB-216763在两种压力下均能减小梗死面积，且在高灌注压力下效果更明显。格列本脲不影响梗死面积，但消除了环孢素A的心脏保护作用，同时对氯化锂包括的心脏保护没有影响。结论灌注压力主要影响GSK-3 β介导的缺血再灌注心脏MPT孔形成的调节。
BACKGROUNDThe mitochondrial permeability transition (MPT) pore may serve as the end-effector of cardio protective mechanisms, namely the mitochondrial K-ATP channels and glycogen synthase kinase-3 beta (GSK-3 beta). 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 K-ATP channels or inhibition of GSK-3 beta and (ii) perfusion pressure modulates the regulation of the MPT pore by mitochondrial K-ATP channels and/or GSK-3 beta.METHODSLangendorff-perfused hearts were subjected to a regional ischemia-reperfusion insult at a perfusion pressure of either 80 or 160 cm H O-2. The perfusion medium contained no drug, diazoxide (80 mu mol/l; mitochondrial K-ATP channel openel lithium chloride (LiCl, 1 mmol/l; nonselective inhibitor of GSK-3 beta), SB-216763 (3 mu mol/l; selective inhibitor of GSK-3 beta), cyclosporine A (0.2 mu mol/l; inhibitor of MPT pore induction), glibenclamide (50 mu mol/l; inhibitor of K-ATP channels), and the combination of cyclosporine A and glibenclamide or the combination of glibenclamide and LiCl.RESULTSThe 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-incluced cardioprotection.CONCLUSIONPerfusion pressure primarily affects GSK-3 beta-mediated regulation of MPT pore formation in the ischemic reperfused heart.