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

1.醛糖还原酶(AR)是多元醇途径中的限速酶，催化葡萄糖还原为山梨醇。该酶还催化氧化损伤不饱和脂肪酸所产生的反应性醛的还原，如4-羟基壬烯醛(HNE)和丙烯醛。在心肌缺血-再灌注过程中，HNE的形成和HNE修饰蛋白的积聚导致组织损伤。因此，AR可能通过减少HNE的积聚而参与晚期缺血预适应的调节。另一方面，AR被报道会加重心脏的缺血再灌注损伤。AR拮抗剂可减轻缺血再灌注损伤，改善缺血时细胞内钠、钙扰动水平。这些观察表明AR在缺血心脏中的作用是相反的。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m…分离的心脏的缺血再灌注损伤。2.在野生型小鼠心脏中，AR抑制剂能显著改善心脏参数、左室舒张末压(LVEDP)和左室压一阶导数正最大值(dp/dtmax)对缺血再灌流的影响。3.在hARTG分离的心脏中，LVEDP升高，dp/dtmax降低，ATP含量降低，肌酸激酶释放显著增加。用AR抑制剂或山梨醇脱氢酶抑制剂(多元醇途径中的第二种酶)预处理可显著改善这些变化。4.共同作用，通过多元醇途径增加流量加剧了过度表达人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。较少

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