Mascareno E, El-Shafei M, Maulik N, Sato M, Guo Y, Das D K, Siddiqui M A
Center for Cardiovascular and Muscle Research, Department of Anatomy and Cell Biology, State University of New York Health Science Center Brooklyn, Brooklyn, NY, USA.
Circulation. 2001 Jul 17;104(3):325-9. doi: 10.1161/01.cir.104.3.325.
Activation of the heart renin-angiotensin system (RAS) under pathophysiological conditions has been correlated with the development of ischemic injury. The binding of angiotensin II to its receptors triggers induction of several, perhaps multifunctional, intracellular signaling pathways, notable among them the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. In this study, we investigated whether the JAK/STAT signaling is involved in the ischemia/reperfusion injury in adult rat myocardium.
We report here that 2 components of the JAK/STAT signaling pathway, namely STAT 5A and STAT 6, are selectively activated in the rat heart subjected to ischemia/reperfusion. The activated STATs bind to a conserved nucleotide sequence (St domain) in the promoter of the angiotensinogen (ANG) gene and consequently upregulate the level of ANG mRNA. Treatment of the hearts with losartan (4.5 micromol/L), an AT(1) blocker, or with tyrphostin AG490 (5 micromol/L), an inhibitor of JAK 2 phosphorylation, results in loss of the STAT/ANG promoter binding activity and an upregulated level of ANG mRNA. Hearts treated with the JAK 2 inhibitor tyrphostin AG490 showed a reduction in myocardial infarct size and in number of cardiomyocytes undergoing apoptosis. The treated hearts also showed a recovery in functional hemodynamics of the myocardium.
These findings suggest that activation of the JAK/STAT signaling pathway is a significant contributing factor to the pathogenesis of myocardial ischemia and that interference in activation of the pathway potentiates recovery in cardiac function.
在病理生理条件下，心脏肾素 - 血管紧张素系统（RAS）的激活与缺血性损伤的发展相关。血管紧张素II与其受体的结合触发了几种可能具有多功能的细胞内信号通路的诱导，其中值得注意的是Janus激酶/信号转导子和转录激活子（JAK/STAT）通路。在本研究中，我们调查了JAK/STAT信号是否参与成年大鼠心肌的缺血/再灌注损伤。
我们在此报告，JAK/STAT信号通路的两个组成部分，即STAT 5A和STAT 6，在遭受缺血/再灌注的大鼠心脏中被选择性激活。活化的STAT与血管紧张素原（ANG）基因启动子中的保守核苷酸序列（St结构域）结合，从而上调ANG mRNA的水平。用氯沙坦（4.5微摩尔/升）（一种AT(1)受体阻滞剂）或用酪氨酸磷酸化抑制剂 tyrphostin AG490（5微摩尔/升）处理心脏，导致STAT/ANG启动子结合活性丧失和ANG mRNA水平上调。用JAK 2抑制剂tyrphostin AG490处理的心脏显示心肌梗死面积减小，凋亡的心肌细胞数量减少。处理后的心脏还显示心肌功能血流动力学恢复。
这些发现表明，JAK/STAT信号通路的激活是心肌缺血发病机制的一个重要因素，对该通路激活的干扰可增强心脏功能的恢复。
