Cardiomyocyte-Specific JunD Overexpression Increases Infarct Size following Ischemia/Reperfusion Cardiac Injury by Downregulating Sirt3
Cardiomyocyte-Specific JunD Overexpression Increases Infarct Size following Ischemia/Reperfusion Cardiac Injury by Downregulating Sirt3
复制标题
DOI：
10.1055/s-0039-3400299
复制
发表时间：
2020-01-01
影响因子：
6.7
通讯作者：
Luscher, Thomas F.
中科院分区：
文献类型：
--
作者：
Akhmedov, Alexander;Montecucco, Fabrizio;Luscher, Thomas F.
急性心肌梗死中的缺血/再灌注（I/R）损伤激活了几种有害的分子机制。转录因子JunD调节参与氧化应激以及细胞增殖、分化和死亡的途径。本研究探讨了JunD在小鼠心脏I/R损伤模型中作为心肌损伤途径调节剂的潜在作用。研究了成年男性心肌I/R后的冠状动脉大小、全身和局部炎症、活性氧的产生以及细胞溶质和线粒体凋亡途径。在野生型（WT）小鼠中，缺血后30分钟和再灌注后24小时，心脏JunD信使核糖核酸表达减少，而JunB增加。心脏特异性JunD过表达小鼠（JunD（Tg/0））与WT相比显示出更大的梗死。然而，缺血后炎症或氧化反应没有差异。JunD过表达通过与其启动子结合减少Sirt 3转录，从而导致线粒体功能障碍、心肌细胞死亡和梗死面积增加。另一方面，JunD沉默减少，而Sirt 3沉默增加梗死面积。在人类心肌尸检标本中，梗死左心室染色内的JunD阳性区域对应于同一心脏连续切片中不可检测的Sirt 3区域。心脏特异性JunD过表达增加I/R后心肌梗死面积这些作用通过Sirt 3转录抑制、线粒体肿胀和细胞凋亡增加介导，表明JunD是心肌I/R损伤的关键调节因子。目前的数据为进一步研究Sirt 3激活作为治疗急性心肌梗死的新靶点的潜在作用奠定了基础。
Ischemia/reperfusion (I/R) injury in acute myocardial infarction activates several deleterious molecular mechanisms. The transcription factor JunD regulates pathways involved in oxidative stress as well as in cellular proliferation, differentiation, and death. The present study investigated the potential role of JunD as a modulator of myocardial injury pathways in a mouse model of cardiac I/R injury. Infarct size, systemic and local inflammation, and production of reactive oxygen species, as well as cytosolic and mitochondrial apoptotic pathways were investigated in adult males after myocardial I/R. In wild-type (WT) mice, 30 minutes after ischemia and up to 24 hours following reperfusion, cardiac JunD messenger ribonucleic acid expression was reduced while JunB increased. Cardiac-specific JunD overexpressing mice ( JunD (Tg/0) ) displayed larger infarcts compared with WT. However, postischemic inflammatory or oxidative responses did not differ. JunD overexpression reduced Sirt3 transcription by binding to its promoter, thus leading to mitochondrial dysfunction, myocardial cell death, and increased infarct size. On the other hand, JunD silencing reduced, while Sirt3 silencing increased infarct size. In human myocardial autopsy specimens, JunD-positive areas within the infarcted left ventricle staining corresponded to undetectable Sirt3 areas in consecutive sections of the same heart. Cardiac-specific JunD overexpression increases myocardial infarct size following I/R. These effects are mediated via Sirt3 transcriptional repression, mitochondrial swelling, and increased apoptosis, suggesting that JunD is a key regulator of myocardial I/R injury. The present data set the stage for further investigation of the potential role of Sirt3 activation as a novel target for the treatment of acute myocardial infarction.