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Paradoxical roles of the aldehyde-metabolizing enzyme, aldose reductase in cardioprotection

醛代谢酶、醛糖还原酶在心脏保护中的矛盾作用

基本信息

批准号：
15590470
负责人：
YABE Chihiro
金额：
$ 2.3万
依托单位：
Kyoto Prefectural University of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590470/
关键词：
aldose reductase heart ischemia-reperfusion injury transgenic mouse 虚血・再灌流障害

项目摘要

1.Aldose reductase (AR) is the rate-limiting enzyme in the polyol pathway that catalyzes the reduction of glucose to sorbitol. The enzyme also catalyzes the reduction of such reactive aldehydes as 4-hydroxynonenal (HNE) and acrolein produced by oxidative damage to unsaturated fatty acids. During myocardial ischemia-reperfusion, the formation of HNE and accumulation of HNE-modified proteins results in tissue damage. AR was thus suggested to act as a mediator of the late phase ischemic preconditioning by attenuating accumulation of HNE. On the other hand, AR is reported to exacerbate ischemia-reperfusion injury of the heart. Inhibitors of AR mitigated the ischemia-reperfusion injury, and improved the levels intracellular sodium and calcium perturbed during ischemia. These observations suggest the opposing roles of AR in the ischemic heart. To clarify the molecular mechanisms underlying these observations, we investigated ischemia-reperfusion injury in the heart isolated from transgenic m … More ice overexpressing human AR (hARTG).2.In wild-type mouse heart pretreatment with AR inhibitors significantly improved perturbation in cardiac parameters, left ventricular end-diastolic pressure (LVEDP) and positive maximal values of the first derivative of left ventricular pressure (dP/dt max), on ischemia-reperfusion. There was no alteration in cardiac AR activity during the time course.3.In the heart isolated from hARTG, higher LVEDP, lower dP/dt max, decreased ATP content and a significant increase in creatine kinase release were observed compared with their littermates on ischemia-reperfusion. These changes were significantly improved by pretreatment with AR inhibitors or an inhibitor of sorbitol dehydrogenase, the second enzyme in the polyol pathway.4.Taken together, enhanced flux through the polyol pathway exacerbated ischemia-reperfusion injury in the myocardium overexpressing human AR. The present findings suggest that the blockade of glucose flux via the polyol pathway is a key element in protection of the ischemic heart. Less

1.醛糖还原酶（AR）是催化葡萄糖还原为山梨醇的多元醇途径中的限速酶。该酶还催化还原反应性醛，如4-羟基壬烯醛（HNE）和丙烯醛产生的氧化损伤不饱和脂肪酸。在心肌缺血-再灌注过程中，HNE的形成和HNE修饰蛋白的积累导致组织损伤。提示AR可能通过减少HNE的蓄积而参与缺血预适应晚期的介导过程。另一方面，据报道AR会加重心脏的缺血-再灌注损伤。AR抑制剂可减轻缺血再灌注损伤，改善缺血时细胞内钠、钙水平的紊乱。这些观察结果表明AR在缺血性心脏中的相反作用。为了阐明这些观察结果背后的分子机制，我们研究了从转基因小鼠分离的心脏缺血再灌注损伤。 ...更多信息 2.在野生型小鼠心脏中，用AR抑制剂预处理显著改善缺血再灌注时心脏参数，左室舒张末压（LVEDP）和左室压力一阶导数的正最大值（dP/dt max）的扰动。心脏AR活性无明显变化。3. hARTG心肌缺血再灌注后LVEDP升高，dP/dt max降低，ATP含量降低，肌酸激酶释放明显增加。这些变化可通过预处理AR抑制剂或山梨醇脱氢酶（多元醇途径中的第二种酶）抑制剂得到显著改善。4.总之，通过多元醇途径的流量增加加重了过表达人AR的心肌的缺血-再灌注损伤。目前的研究结果表明，通过多元醇途径阻断葡萄糖流量是保护缺血心脏的关键因素。少