Aldose reductase mediates myocardial ischemia-reperfusion injury in part by opening mitochondrial permeability transition pore
Aldose reductase mediates myocardial ischemia-reperfusion injury in part by opening mitochondrial permeability transition pore
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DOI：
10.1152/ajpheart.01012.2008
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发表时间：
2009-02-01
影响因子：
4.8
通讯作者：
Ramasamy, Ravichandran
中科院分区：
文献类型：
--
作者：
Ananthakrishnan, Radha;Kaneko, Michiyo;Ramasamy, Ravichandran
Ananthakrishnan R、Kaneko M、Hwang YC、Quadri N、Gomez T、Li Q、Caspersen C、Ramasamy R.醛糖还原酶部分通过开放线粒体通透性转换孔介导心肌缺血再灌注损伤。Am J Physiol心脏圈Physiol 296：H333-H341,2009。2008年12月5日首次出版；DOI：10.1152/ajpheart.01012.2008。-醛糖还原酶(AR)是醛酮还原酶家族的成员，已被证明在介导心肌缺血-再灌注(I/R)损伤中发挥核心作用。最近，利用广泛过量表达人AR(ARTg)的转基因小鼠，我们证实AR是心肌I/R损伤的重要组成部分，抑制该酶可以保护心脏免受I/R损伤(20-22，48，49，56)。为了明确AR通路影响心肌缺血损伤的机制，我们研究了ARTg或野生型(WT)在心肌I/R后的活性氧(ROS)、抗氧化酶和线粒体通透性转换(MPT)孔开度所起的作用，以线粒体摄取2-脱氧葡萄糖比率来确定I/R后MPT孔开度，而H_2O_2作为ROS的关键指标。ARTg组小鼠心肌2-脱氧葡萄糖摄取率和钙诱导的线粒体肿胀显著高于WT组。在ARTg小鼠心脏I/R过程中，用环孢菌素A阻断MPT孔可明显减轻心肌缺血损伤。H_2O_2测量表明，ARTg小鼠心脏I/R后线粒体ROS的生成明显高于WT小鼠。此外，ARTg线粒体中的抗氧化剂GSH水平显著低于WT。白藜芦醇处理或AR的药物阻断显著减少了ARTg小鼠心脏I/R应激下线粒体ROS的生成和MPT孔洞的开放。本研究表明，MPT孔道开放是AR通路介导心肌I/R损伤的关键事件，而ARTg小鼠心脏中ROS生成的增加在一定程度上触发了I/R后MPT孔道的开放。因此，抑制AR通路对线粒体的保护作用可能是挽救缺血心肌的有效辅助手段。
Ananthakrishnan R, Kaneko M, Hwang YC, Quadri N, Gomez T, Li Q, Caspersen C, Ramasamy R. Aldose reductase mediates myocardial ischemia-reperfusion injury in part by opening mitochondrial permeability transition pore. Am J Physiol Heart Circ Physiol 296: H333-H341, 2009. First published December 5, 2008; doi:10.1152/ajpheart.01012.2008.-Aldose reductase (AR), a member of the aldo-keto reductase family, has been demonstrated to play a central role in mediating myocardial ischemia-reperfusion (I/R) injury. Recently, using transgenic mice broadly overexpressing human AR (ARTg), we demonstrated that AR is an important component of myocardial I/R injury and that inhibition of this enzyme protects heart from I/R injury (20-22, 48, 49, 56). To rigorously delineate mechanisms by which AR pathway influences myocardial ischemic injury, we investigated the role played by reactive oxygen species (ROS), antioxidant enzymes, and mitochondrial permeability transition (MPT) pore opening in hearts from ARTg or littermates [wild type (WT)] subjected to I/R. MPT pore opening after I/R was determined using mitochondrial uptake of 2-deoxyglucose ratio, while H2O2 was measured as a key indicator of ROS. Myocardial 2-deoxy-glucose uptake ratio and calcium-induced swelling were significantly greater in mitochondria from ARTg mice than in WT mice. Blockade of MPT pore with cyclosphorin A during I/R reduced ischemic injury significantly in ARTg mice hearts. H2O2 measurements indicated mitochondrial ROS generation after I/R was significantly greater in ARTg mitochondria than in WT mice hearts. Furthermore, the levels of antioxidant GSH were significantly reduced in ARTg mitochondria than in WT. Resveratrol treatment or pharmacological blockade of AR significantly reduced ROS generation and MPT pore opening in mitochondria of ARTg mice hearts exposed to I/R stress. This study demonstrates that MPT pore opening is a key event by which AR pathway mediates myocardial I/R injury, and that the MPT pore opening after I/R is triggered, in part, by increases in ROS generation in ARTg mice hearts. Therefore, inhibition of AR pathway protects mitochondria and hence may be a useful adjunct for salvaging ischemic myocardium.