Boengler Kerstin, Hilfiker-Kleiner Denise, Drexler Helmut, Heusch Gerd, Schulz Rainer
Institut für Pathophysiologie, Universitätsklinikum Essen, Germany.
Pharmacol Ther. 2008 Nov;120(2):172-85. doi: 10.1016/j.pharmthera.2008.08.002. Epub 2008 Aug 23.
Proteins of the interleukin-6 (IL-6) family bind to receptors in the plasma membrane. Subsequent signal transduction involves activation of the janus kinase (JAK) and signal transducer and activator of transcription (STAT) proteins. STAT proteins are translocated into the nucleus, where they bind to the promoter region of target genes and are thereby involved in regulating the transcription of target genes. In the first part, the present review focusses on the role of STAT3 in ischemia/reperfusion injury and in cardioprotection by ischemic pre- and postconditioning. In the heart, ischemia induces an increase in IL-6 cytokines, which is associated with activation of STAT3. Genetic modification of the myocardial STAT3 protein content shows a protective role of STAT3 on infarct size after ischemia/reperfusion injury. The cardioprotection by both early and late ischemic preconditioning as well as by ischemic postconditioning involves an activation of STAT3 and is dependent on STAT3 protein level. Whereas the infarct-sparing effect of late preconditioning is clearly mediated by an increase in transcription-mediated protein synthesis, early preconditioning is independent of gene transcription, suggesting a role of STAT3 independent of transcriptional regulation. Possibly, STAT3 plays a role in modifying mitochondrial function, organelles central for the cardioprotection by pre- and postconditioning. In the second part, the role of STAT3 in physiological stresses such as aging and pregnancy, as well as in pathophysiological situations such as myocardial infarction and heart failure is summarized. Furthermore, the requirements for the use of STAT3 as a target for treatment strategies of cardiovascular diseases is discussed.
白细胞介素-6（IL-6）家族的蛋白质与质膜中的受体结合。随后的信号转导涉及Janus激酶（JAK）以及信号转导和转录激活因子（STAT）蛋白的激活。STAT蛋白会转移至细胞核，在细胞核中它们与靶基因的启动子区域结合，从而参与调控靶基因的转录。在第一部分中，本综述聚焦于STAT3在缺血/再灌注损伤以及缺血预处理和后处理所带来的心脏保护中的作用。在心脏中，缺血会导致IL-6细胞因子增加，这与STAT3的激活有关。对心肌STAT3蛋白含量进行基因改造后发现，STAT3在缺血/再灌注损伤后对梗死面积具有保护作用。早期和晚期缺血预处理以及缺血后处理所带来的心脏保护作用均涉及STAT3的激活，且依赖于STAT3蛋白水平。虽然晚期预处理的梗死面积缩小效应明显是由转录介导的蛋白质合成增加所介导的，但早期预处理则与基因转录无关，这表明STAT3的作用独立于转录调控。STAT3可能在改变线粒体功能方面发挥作用，而线粒体是预处理和后处理实现心脏保护作用的核心细胞器。在第二部分中，总结了STAT3在衰老和妊娠等生理应激以及心肌梗死和心力衰竭等病理生理状况中的作用。此外，还讨论了将STAT3用作心血管疾病治疗策略靶点的相关要求。
