RNA interference targeting SHP-1 attenuates myocardial infarction in rats
RNA interference targeting SHP-1 attenuates myocardial infarction in rats
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DOI：
10.1096/fj.05-4020fje
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发表时间：
2005-10-01
期刊：
影响因子：
4.8
通讯作者：
Makino, N
中科院分区：
文献类型：
--
作者：
Sugano, M;Tsuchida, K;Makino, N
含有 Src 同源结构域 2 (SH2) 的酪氨酸磷酸酶-1 (SHP-1) 在细胞凋亡和降低 Akt 磷酸化中发挥关键作用。心肌细胞凋亡被认为导致急性心肌梗死 (AMI) 面积增加，而 Akt 激活在缺血后发挥强大的心脏保护作用。因此，旨在抑制 SHP-1 表达的治疗策略对于 AMI 将是有益的。在这里，我们报道了针对 SHP-1 的 siRNA 减少了 AMI 大鼠模型中的梗塞面积。注射到缺血的左心室壁后，基于载体的 siRNA 显着抑制了 SHP-1 mRNA 和 SHP-1 蛋白水平的增加。 siRNA载体还显着减少了与Fas-R结合的SHP-1。与乱序 siRNA 载体相比，SHP-1 siRNA 载体增加了磷酸化 Akt，并减少了 DNA 片段化和 caspase 活性。最后，在LCA连接后2天，使用SHP-1 siRNA载体的心肌梗塞面积明显小于使用乱序siRNA载体的心肌梗塞面积。总之，心脏中的SHP-1从AMI早期开始增加，这种增加被认为有助于心肌梗塞面积的增加。使用 SHP-1 siRNA 载体抑制 SHP-1 可显着减少 AMI 中的梗塞面积。
The Src homology domain 2 (SH2)-containing tyrosine phosphatase- 1 (SHP-1) plays a key role in apoptosis and decreases phosphorylation of Akt. Apoptosis of cardiomyocytes is thought to contribute to the increased area of acute myocardial infarction ( AMI), and Akt activation exerts a powerful cardioprotective effect after ischemia. Thus, a therapeutic strategy designed to inhibit expression of SHP-1 would be beneficial in AMI. Here we report that siRNA targeting SHP-1 reduced infarct size in a rat model of AMI. Upon injection into the ischemic left ventricular wall, the vector-based siRNA significantly suppressed the increase in the SHP-1 mRNA and the SHP-1 protein levels. The siRNA vector also significantly reduced the SHP-1 that bound to Fas-R. The SHP-1 siRNA vector increased phospho-Akt and reduced DNA fragmentation and caspase activity compared with the scramble siRNA vector. Finally, the area of myocardial infarction was significantly smaller with the SHP-1 siRNA vector than with the scramble siRNA vector at 2 days after LCA ligation. In conclusion, SHP-1 in the heart increased from the early stage of AMI, and this increase was thought to contribute to the increased area of myocardial infarction. Suppression of SHP-1 with the SHP-1 siRNA vector markedly reduced the infarct size in AMI.