Sugano Masahiro, Tsuchida Keiko, Hata Tomoji, Makino Naoki
Department of Molecular and Cellular Biology, Division of Molecular and Clinical Gerontology, Medical Institute of Bioregulation, Kyushu University, Beppu, Oita, Japan.
FASEB J. 2005 Dec;19(14):2054-6. doi: 10.1096/fj.05-4020fje. Epub 2005 Oct 13.
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.
含Src同源结构域2（SH2）的酪氨酸磷酸酶-1（SHP-1）在细胞凋亡中起关键作用，并降低Akt的磷酸化水平。心肌细胞凋亡被认为会导致急性心肌梗死（AMI）面积增大，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AMI有益。在此我们报告，靶向SHP-1的小干扰RNA（siRNA）在大鼠AMI模型中减小了梗死面积。将基于载体的siRNA注射到缺血的左心室壁后，其显著抑制了SHP-1信使核糖核酸（mRNA）和SHP-1蛋白水平的升高。siRNA载体还显著降低了与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水平，减少了DNA片段化和半胱天冬酶活性。最后，在结扎左冠状动脉（LCA）2天后，SHP-1 siRNA载体组的心肌梗死面积明显小于乱序siRNA载体组。总之，心脏中的SHP-1在AMI早期即升高，这种升高被认为会导致心肌梗死面积增大。用SHP-1 siRNA载体抑制SHP-1可显著减小AMI的梗死面积。
