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Elucidation of the Molecular Mechanism of Cardiac Response to the Ischemia Reperfusion Stresses and Establishment of Treatment Based on the Molecular Mechanism

阐明心脏对缺血再灌注应激反应的分子机制并建立基于分子机制的治疗方法

基本信息

批准号：
09470162
负责人：
SEKO Yoshinori
金额：
$ 9.6万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

项目摘要

1. Molecular mechanism of cardiac response to hypoxia/reoxygenation : We showed that hypoxia/reoxygenation activated Src family tyrosine kinases, p21^<ras>, three MAPK family member kinases and their upstream as well as downstream kinases, Jak/STAT tyrosine kinases, and a transcription factor ATF-2. The signal transduction cascades activated by these stimuli were at least partly different. 2. Autocrine mechanism via certain humoral factors involved in the activation of intracellular signaling induced by hypoxia/reoxygenation : (A)We showed that the activation of intracellular signaling in cardiac myocytes induced by hypoxia was mediated by VEGF in an autocrine fashion. This autocrine mechanism seemed to play a protective role in cardiac response to hypoxic stresses by suppressing apoptotic process and increasing adhesion between cardiac myocytes and extracellular matrix. (B)We found that similar autocrine mechanism was involved in the activation of intracellular signaling in cardiac my … More ocytes induced by reoxygenation, and we are now isolating and purifying the humoral factor. 3. Molecular mechanism of cardiac response to relative hypoxia : We showed that the activation of intracellular signaling in cardiac myocytes induced by pulsatile mechanical stretch (relative hypoxia) was also mediated by VEGF in an autocrine fashion. 4. Serum levels of the humoral factor, which mediates cardiac response to ischemia/reperfusion(hypoxia/reoxygenation) : (A)By meas uring the serum levels of VEGF in patients with acute myocardial infarction undergoing early reperfusion therapy, we demonstrated that VEGF could be a sensitive indicator of ischemic (hypoxic) state. This also strongly supported the data of 2. (A). (B)We are now isolating and purifying the humoral factor involved in the activation of intracellular signaling induced by reoxygenation, and we suppose that the serum levels of the humaral factor will be a good indicator of reperfused (reoxygenated) state in the heart of these patients. Less

1. 心脏对缺氧/再氧化反应的分子机制：我们发现缺氧/再氧化激活了Src家族酪氨酸激酶，p21^<ras>，三个MAPK家族成员激酶及其上游和下游激酶，Jak/STAT酪氨酸激酶和转录因子ATF-2。这些刺激激活的信号转导级联至少部分不同。2. 通过某些体液因子参与缺氧/再氧化诱导的细胞内信号激活的自分泌机制：(A)我们发现缺氧诱导的心肌细胞内信号激活是由VEGF以自分泌方式介导的。这种自分泌机制似乎通过抑制凋亡过程和增加心肌细胞与细胞外基质之间的粘附，在心脏对缺氧应激的反应中发挥保护作用。(B)我们发现类似的自分泌机制参与了心肌细胞内信号的激活，更多的细胞被再氧化诱导，我们现在正在分离和纯化体液因子。3. 心脏对相对缺氧反应的分子机制：我们发现搏动性机械拉伸（相对缺氧）诱导的心肌细胞内信号的激活也由VEGF以自分泌方式介导。4. 介导心脏缺血/再灌注（缺氧/再氧）反应的体液因子的血清水平：(A)通过测量急性心肌梗死患者早期再灌注治疗的血清VEGF水平，我们证明VEGF可能是缺血（缺氧）状态的敏感指标。这也有力地支持了2。(A) (B)我们现在正在分离和纯化参与再氧化诱导的细胞内信号激活的体液因子，我们认为血清中体液因子的水平将是这些患者心脏再灌注（再氧化）状态的良好指标。少