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力预测因子。在这两种疾病中，恶病质的病理机制可能包括炎症和外周器官功能障碍，这与疾病的严重程度和临床结果相关，并导致心脏萎缩。心力衰竭患者收缩功能下降的部分原因是肌球蛋白重链(MHC)蛋白含量和功能的减少。我们观察到，在扩张型心肌病(DCM)和围产期心肌病(PPCM)中，以STAT3低表达为特征的microRNA-199a-5p(miR-199a)的表达增加。MiRNA-199a的上调损害了心肌细胞中a-和bMHC的转录，导致与肌节组织丢失相关的MHC水平降低。A-和bMHC转录的下降是由miR-199a介导的对泛素结合酶(Ube)2i、2g1和2o的抑制引起的。与STAT3、miR-199a和Ube2o酶之间的联系一致，心肌梗死(MI)后缺乏gp130介导的STAT3激活的小鼠缺乏MI诱导的Ube2o上调，并表现出较低的心脏MHC总含量。我们观察到，不仅STAT3的低表达而且STAT3的持续高激活影响心脏a-和bMHC的表达，而且主要是在转录后水平。这种情况出现在因结肠-26腺瘤或B16-F10黑色素瘤导致心脏萎缩的小鼠身上。在患有B16-F10的小鼠中，STAT3的高水平和持续激活与心功能下降以及a-和bMHC蛋白含量下降有关，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-199a在这些肿瘤小鼠的心脏中减少。蛋白质组学显示，Anagomir介导的心肌细胞miR-199a正常表达的减少促进了泛素蛋白酶体系统(UPS)介导的a-和bMHC的降解。这些特征可能是诱导心脏高STAT3激活的肿瘤类型所特有的，因为肝癌小鼠既没有STAT3激活，也没有心脏萎缩或心肌MHC蛋白丢失。我们假设，在两个方向上损害心肌细胞中STAT3调节的条件，无论是过低还是过高，都会引起心肌细胞肌节MHC蛋白的病理生理变化。这些与STAT3相关的机制似乎影响心脏MHC蛋白的功能和周转，从而可能影响心肌细胞的功能、几何形状和存活。在本项目中，我们的目标是了解STAT3信号与MI后、DCM和PPCM中的a-和bMHC蛋白的调节以及肿瘤引起的心脏萎缩的潜在分子机制。同时，我们将调查参与这些回路的分子是否可能成为上述心脏疾病类型的合适的新治疗靶点。

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.