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

1.心脏对缺氧/复氧反应的分子机制：我们发现缺氧/复氧激活Src家族酪氨酸激酶、p21^<ras>、三种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/复氧诱导的细胞内信号转导激活的自分泌机制：（A）我们表明，缺氧诱导的心肌细胞内信号转导激活由VEGF以自分泌方式介导。这种自分泌机制可能通过抑制心肌细胞凋亡和增加心肌细胞与细胞外基质的粘附，在心肌对缺氧应激的反应中起保护作用。(B)We发现类似的自分泌机制参与了心肌细胞内信号的激活， 关于我们 细胞诱导复氧，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，由脉动机械牵张（相对缺氧）诱导的心肌细胞内信号传导的激活也由VEGF以自分泌方式介导。4.体液因子的血清水平，其介导对缺血/再灌注（缺氧/复氧）的心脏反应：（A）通过测量接受早期再灌注治疗的急性心肌梗死患者中VEGF的血清水平，我们证明VEGF可以是缺血（缺氧）状态的敏感指标。这也有力地支持了2.（一）. (B)We目前正在分离和纯化参与由再氧合诱导的细胞内信号传导激活的体液因子，并且我们假设体液因子的血清水平将是这些患者心脏中再灌注（再氧合）状态的良好指示剂。少

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