| Project/Area Number |
15590470
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Applied pharmacology
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| Research Institution | Kyoto Prefectural University of Medicine |
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Principal Investigator |
YABE Chihiro Kyoto Prefectural University of Medicine, Graduate School of Medicine, Professor, 医学研究科, 教授 (70150571)
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| Co-Investigator(Kenkyū-buntansha) |
IWATA Kazumi Kyoto Prefectural University of Medicine, Graduate School of Medicine, Instructor, 医学研究科, 助手 (60305571)
KATSUYAMA Masato Kyoto Prefectural University of Medicine, Graduate School of Medicine, Instructor, 医学研究科, 助手 (60315934)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2004: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 2003: ¥3,000,000 (Direct Cost: ¥3,000,000)
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| Keywords | aldose reductase / heart / ischemia-reperfusion injury / transgenic mouse / 虚血・再灌流障害 |
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| Research Abstract |
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
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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
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