STSTAT3 regulates via microRNAs and the ubiquitin proteasomal system the homeostasis of sarcomeric myosin heavy chain proteins and impacts thereby on cardiac hypertrophy and atrophyAT3, a potential key regulator of sarcomeric myosin heavy chain proteins i

恶病质是心力衰竭和晚期癌症患者发病率和死亡率的有效预测因子。两种疾病类型中恶病质状况的病理机制可能包括炎症和外周器官功能障碍，其与疾病严重程度和临床结果相关并导致心脏萎缩。心力衰竭患者的收缩功能降低部分是由肌球蛋白重链（MHC）蛋白含量和功能降低引起的。我们观察到，在扩张型心肌病（DCM）和围产期心肌病（PPCM），其特征在于低STAT 3表达，microRNA-199 a-5 p（miR-199 a）的表达增加。miRNA-199 a的上调损害心肌细胞中a-和bMHC的转录，导致与肌节组织损失相关的MHC水平降低。a-和bMHC转录的减少是由miR-199 a介导的泛素缀合酶（Ube）2 i、2g 1和2 o的抑制引起的。与STAT 3、miR-199 a和Ube 20酶之间的联系一致，心肌梗死（MI）后缺乏gp 130介导的STAT 3激活的小鼠缺乏MI后诱导的Ube 20上调，并显示出较低的总心脏MHC含量。我们观察到，不仅低的STAT 3表达，而且持续的高活化的STAT 3影响心脏的a-和bMHC的表达，但主要是在转录后水平。这种情况存在于由于结肠-26腺瘤或B16-F10黑色素瘤肿瘤而导致心脏萎缩的小鼠中。在患有B16-F10的小鼠中，STAT 3的高度和持续激活与心脏功能降低以及a-和bMHC蛋白含量降低相关，而其他肌节蛋白如肌钙蛋白T或原肌球蛋白不受影响。我们发现miR-199 a在这些肿瘤小鼠的心脏中减少。蛋白质组学研究表明，在心肌细胞中，西洛莫介导的正常miR-199 a表达的减少促进了泛素蛋白体系统（UPS）介导的a-和bMHC降解的增强。这些特征可能对在心脏中诱导高STAT 3激活的肿瘤类型具有特异性，因为患有肝癌肿瘤的小鼠既不显示STAT 3激活，也不显示心脏萎缩或心脏MHC蛋白的丢失。我们假设，心肌细胞中STAT 3的调节在两个方向上都受到损害的条件，无论是太低还是太高，都会引起心肌细胞中肌节MHC蛋白的病理生理学改变。这些STAT 3相关机制似乎会影响心脏MHC蛋白的功能和转换，从而可能影响心肌细胞的功能、几何形状和生存。在本项目中，我们的目标是了解潜在的分子机制，连接STAT 3信号转导的调制后，心肌梗死，在DCM和PPCM和肿瘤诱导的心脏萎缩的a-和bMHC蛋白。同时，我们将研究这些回路中涉及的分子是否可能是上述心脏疾病类型中合适的新治疗靶点。

Cachexia is a potent predictor of morbidity and mortality in patients with heart failure and advanced cancer. Pathological mechanisms in cachectic conditions in both disease types may include inflammation and peripheral organ dysfunction, which correlate with disease severity and clinical outcome and lead to cardiac atrophy. Reduced contractile function in patients with heart failure is in part caused by a decrease in myosin heavy chain (MHC) protein content and functionality. We observed that in dilated cardiomyopathy (DCM) and in peripartum cardiomyopathy (PPCM), characterized by low STAT3 expression, increased expression of microRNA-199a-5p (miR-199a) is present. Upregulation of miRNA-199a impairs the transcription of a- and bMHC in cardiomyocytes leading to decreased MHC levels associated with a loss in sarcomere organization. The decrease in a- and bMHC transcription is caused by a miR-199a-mediated suppression of the ubiquitin conjugating enzymes (Ube)2i, 2g1 and 2o. Consistent with a link between STAT3, miR-199a and the Ube2o enzyme, mice that lack gp130-mediated STAT3 activation after myocardial infarction (MI) lack post MI induced upregulation of Ube2o and display lower total cardiac MHC content. We observed that not only low STAT3 expression but also continuous high activation of STAT3 affects cardiac a- and bMHC expression but mainly at the posttranscriptional level. Such a situation is present in mice with cardiac atrophy due to colon-26 adenoma or B16-F10 melanoma tumors. In mice with B16-F10 the high and continuous activation of STAT3 is associated with reduced cardiac function and a decrease in a- and bMHC protein content, while other sarcomeric proteins such as Troponin T or Tropomyosin are not affected. We found that miR-199a is reduced in hearts of these tumor mice. Proteomics revealed that antagomir-mediated reduction of normal miR-199a expression in cardiomyocytes promotes enhanced ubiquitin proteosomal system (UPS)-mediated degradation of a- and bMHC. These features may be specific for tumor types that induce high STAT3 activation in the heart, since mice with a hepatoma tumor show neither STAT3 activation, nor cardiac atrophy or loss of cardiac MHC protein. We hypothesize that conditions that impair the regulation of STAT3 in cardiomyocytes in both directions, either too low or too high, evoke pathophysiological alterations in sarcomeric MHC proteins in cardiomyocytes. These STAT3 related mechanisms seem to affect functionality and turnover of cardiac MHC proteins and may thereby impact on cardiomyocyte function, geometry and survival. In the present project, we aim to understand the underlying molecular mechanisms that link STAT3 signaling to modulations of a- and bMHC proteins after MI, in DCM and in PPCM and in tumor induced cardiac atrophy. In parallel, we will investigate if molecules involved in these circuits may be suitable novel therapeutic targets in the cardiac disease types mentioned above.