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

1.醛糖还原酶（AR）是多元醇途径中催化葡萄糖还原为山梨醇的限速酶。该酶还催化不饱和脂肪酸氧化损伤产生的4-羟基壬烯醛（HNE）和丙烯醛等活性醛的还原。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。因此，AR可能通过减少HNE的积累而起到晚期缺血预处理的中介作用。另一方面，据报道AR会加重心脏缺血再灌注损伤。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紊乱。这些观察结果表明AR在缺血心脏中的相反作用。为了阐明这些观察结果的分子机制，我们研究了从转基因小鼠分离的心脏缺血-再灌注损伤。在野生型小鼠心脏预处理中，AR抑制剂显著改善心肌参数的扰动，左室舒张末期压（LVEDP）和左室压一阶导数（dP/dt max）的阳性最大值，缺血-再灌注。在时间过程中，心脏AR活动无明显改变。与同窝鼠相比，hARTG分离的心脏在缺血-再灌注时LVEDP升高，dP/dt max降低，ATP含量降低，肌酸激酶释放显著增加。用AR抑制剂或山梨糖醇脱氢酶（多元醇途径中的第二种酶）抑制剂预处理后，这些变化显著改善。综上所述，通过多元醇途径增强的葡萄糖通量加剧了过度表达人类AR的心肌缺血-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通量是保护缺血心脏的关键因素。少

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