Doudin Asmma, Riebeling Theresa, Staab Julia, Menon Priyanka Rajeev, Lühder Fred, Wirths Oliver, Vinkemeier Uwe, Ivetic Aleksandar, Meyer Thomas
Department of Psychosomatic Medicine and Psychotherapy, University Medical Centre Göttingen, and German Centre for Cardiovascular Research (DZHK), Partner Site Göttingen, Göttingen, Germany.
Department of Nephrology and Hypertension, University Hospital Schleswig-Holstein, Kiel, Germany.
Front Cardiovasc Med. 2023 Feb 27;10:975012. doi: 10.3389/fcvm.2023.975012. eCollection 2023.
In this study, we addressed the functional significance of co-operative DNA binding of the cytokine-driven transcription factor STAT1 (signal transducer and activator of transcription 1) in an experimental murine model of acute myocardial infarction (MI). STAT1 knock-in mice expressing a phenylalanine-to-alanine substitution at position 77 in the STAT1 amino-terminal domain were examined for the early clinical effects produced by ligation of the left anterior descending coronary artery (LAD), an established model for MI. The F77A mutation has been previously reported to disrupt amino-terminal interactions between adjacent STAT1 dimers resulting in impaired tetramerization and defective co-operative binding on DNA, while leaving other protein functions unaffected. Our results demonstrate that a loss of STAT1 tetramer stabilization improves survival of adult male mice and ameliorates left ventricular dysfunction in female mice, as determined echocardiographically by an increased ejection fraction and a reduced left intra-ventricular diameter. We found that the ratio of STAT3 to STAT1 protein level was higher in the infarcted tissue in knock-in mice as compared to wild-type (WT) mice, which was accompanied by an enhanced infiltration of immune cells in the infarcted area, as determined by histology. Additionally, RNA sequencing of the infarcted tissue 24 h after LAD ligation revealed an upregulation of inflammatory genes in the knock-in mice, as compared to their WT littermates. Concomitantly, genes involved in oxidative phosphorylation and other metabolic pathways showed a significantly more pronounced downregulation in the infarcted tissue from STAT1 mice than in WT animals. Based on these results, we propose that dysfunctional STAT1 signalling owing to a lack of oligomerisation results in a compensatory increase in STAT3 expression and promotes early infiltration of immune cells in the infarcted area, which has beneficial effects on left ventricular remodelling in early MI following LAD ligation.
在本研究中，我们在急性心肌梗死（MI）的实验性小鼠模型中探讨了细胞因子驱动的转录因子STAT1（信号转导子和转录激活子1）协同DNA结合的功能意义。对在STAT1氨基末端结构域第77位表达苯丙氨酸至丙氨酸取代的STAT1基因敲入小鼠，检查了通过结扎左冠状动脉前降支（LAD）产生的早期临床效应，LAD结扎是一种公认的MI模型。先前报道F77A突变会破坏相邻STAT1二聚体之间的氨基末端相互作用，导致四聚化受损和DNA上的协同结合缺陷，而其他蛋白质功能不受影响。我们的结果表明，STAT1四聚体稳定性的丧失提高了成年雄性小鼠的存活率，并改善了雌性小鼠的左心室功能障碍，这通过超声心动图测定为射血分数增加和左心室内径减小。我们发现，与野生型（WT）小鼠相比，基因敲入小鼠梗死组织中STAT3与STAT1蛋白水平的比率更高，组织学检查确定梗死区域免疫细胞浸润增强。此外，LAD结扎后24小时梗死组织的RNA测序显示，与同窝野生型小鼠相比，基因敲入小鼠中炎症基因上调。同时，与野生型动物相比，参与氧化磷酸化和其他代谢途径的基因在STAT1小鼠梗死组织中的下调明显更明显。基于这些结果，我们提出，由于缺乏寡聚化导致的STAT1信号功能障碍会导致STAT3表达的代偿性增加，并促进梗死区域免疫细胞的早期浸润，这对LAD结扎后早期MI的左心室重塑具有有益作用。
