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

1.心脏对低氧/复氧反应的分子机制：我们发现低氧/复氧激活了Src家族酪氨酸激酶、三个MAPK家族成员及其上游和下游的激酶、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有部分不同。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的激活是由血管内皮生长因子以自分泌的方式介导的。这种自分泌机制可能通过抑制心肌细胞的凋亡和增加心肌细胞与细胞外基质之间的黏附而在心脏对低氧应激的反应中起到保护作用。(B)我们发现类似的自分泌机制参与了心脏My…细胞内信号的激活通过复氧诱导更多的细胞，我们现在正在分离和纯化体液因子。3.心脏对相对低氧反应的分子机制：我们发现脉动机械牵张(相对低氧)诱导的心肌细胞内信号的激活也是由血管内皮生长因子以自分泌的方式介导的。4.血清中介导心脏对缺血/再灌注(缺氧/复氧)反应的体液因子水平：(A)通过检测急性心肌梗死早期再灌注治疗患者血清中血管内皮生长因子的水平，证明血管内皮生长因子可作为反映心肌缺血(缺氧)状态的敏感指标。这也有力地支持了2.(A)的数据。(B)我们现正分离和提纯参与复氧诱导的细胞内信号激活的体液因子，我们认为血清中的体液因子水平将是这些患者心脏再灌流(复氧)状态的良好指标。较少

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