Ananthakrishnan Radha, Kaneko Michiyo, Hwang Yuying C, Quadri Nosirudeen, Gomez Teodoro, Li Qing, Caspersen Casper, Ramasamy Ravichandran
Division of Surgical Science , Department of Surgery, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
Am J Physiol Heart Circ Physiol. 2009 Feb;296(2):H333-41. doi: 10.1152/ajpheart.01012.2008. Epub 2008 Dec 5.
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-deoxyglucose 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.
醛糖还原酶（AR）是醛酮还原酶家族的一员，已被证明在介导心肌缺血再灌注（I/R）损伤中起核心作用。最近，我们利用广泛过表达人AR的转基因小鼠（ARTg）证明，AR是心肌I/R损伤的重要组成部分，抑制这种酶可保护心脏免受I/R损伤（20 - 22、48、49、56）。为了严格阐明AR途径影响心肌缺血损伤的机制，我们研究了活性氧（ROS）、抗氧化酶和线粒体通透性转换（MPT）孔开放在接受I/R的ARTg或同窝小鼠[野生型（WT）]心脏中的作用。I/R后MPT孔开放通过线粒体对2-脱氧葡萄糖摄取率来确定，而H2O2作为ROS的关键指标进行测量。ARTg小鼠线粒体中的心肌2-脱氧葡萄糖摄取率和钙诱导肿胀明显高于WT小鼠。在I/R期间用环孢菌素A阻断MPT孔可显著降低ARTg小鼠心脏的缺血损伤。H2O2测量表明，I/R后ARTg线粒体中的线粒体ROS生成明显高于WT小鼠心脏。此外，ARTg线粒体中的抗氧化剂谷胱甘肽（GSH）水平明显低于WT。白藜芦醇治疗或AR的药理学阻断可显著降低暴露于I/R应激的ARTg小鼠心脏线粒体中的ROS生成和MPT孔开放。本研究表明，MPT孔开放是AR途径介导心肌I/R损伤的关键事件，I/R后的MPT孔开放部分是由ARTg小鼠心脏中ROS生成增加触发的。因此，抑制AR途径可保护线粒体，从而可能是挽救缺血心肌的有用辅助手段。
